研究者詳細 - 小崎　健次郎

論文 - 小崎　健次郎

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De novo 2q36.3q37.1 deletion encompassing TRIP12 and NPPC yields distinct phenotypes

Kondo Y., Aoyama K., Suzuki H., Hattori A., Hori I., Ito K., Yoshida A., Koroki M., Ueda K., Kosaki K., Saitoh S.

Human Genome Variation （Human Genome Variation） 7 （ 1 ） 2020年12月

© 2020, The Author(s). We report a patient with developmental delay, extremely short stature, small hands, dysmorphic facial features, hearing loss, and epilepsy carrying a de novo 2.76-Mb deletion of 2q36.3q37.1, including TRIP12 and NPPC. TRIP12 haploinsufficiency causes developmental delay with isolated dysmorphic facial features, whereas NPPC haploinsufficiency causes short stature and small hands. This is the first report of a unique phenotype, which is secondary to a microdeletion encompassing TRIP12 and NPPC.

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Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association

Fujinami-Yokokawa Y., Fujinami K., Kuniyoshi K., Hayashi T., Ueno S., Mizota A., Shinoda K., Arno G., Pontikos N., Yang L., Liu X., Sakuramoto H., Katagiri S., Mizobuchi K., Kominami T., Terasaki H., Nakamura N., Kameya S., Yoshitake K., Miyake Y., Kurihara T., Tsubota K., Miyata H., Iwata T., Tsunoda K., Nishimura T., Hayashizaki Y., Kondo M., Shimozawa N., Horiguchi M., Yamamoto S., Kuze M., Naoi N., Machida S., Shimada Y., Nakamura M., Fujikado T., Hotta Y., Takahashi M., Mochizuki K., Murakami A., Kondo H., Ishida S., Nakazawa M., Hatase T., Matsunaga T., Maeda A., Noda K., Tanikawa A., Yamamoto S., Yamamoto H., Araie M., Aihara M., Nakazawa T., Sekiryu T., Kashiwagi K., Kosaki K., Piero C., Fukuchi T., Hayashi A., Hosono K., Mori K., Tanaka K., Furuya K., Suzuki K., Kohata R., Yanagi Y., Minegishi Y., Iejima D., Suga A., Rossmiller B.P., Pan Y., Oshima T., Nakayama M., Teruyama Y., Yamamoto M., Minematsu N., Sanbe H., Mori D., Kijima Y., Mawatari G., Kurata K., Yamada N., Itoh M., Kawaji H., Murakawa Y.

Scientific Reports （Scientific Reports） 10 （ 1 ） 2020年12月

© 2020, The Author(s). Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15–77/25–94). The median visual acuity in the right/left eye was 0.52/0.40 (range, −0.08–2.00/−0.18–1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population.

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A Japanese girl with mild xeroderma pigmentosum group D neurological disease diagnosed using whole-exome sequencing

Yokoi T., Enomoto Y., Uehara T., Kosaki K., Kurosawa K.

Human Genome Variation （Human Genome Variation） 7 （ 1 ） 2020年12月

© 2020, The Author(s). We report a Japanese girl with mild xeroderma pigmentosum group D neurological disease. She had short stature, cataracts, intellectual disability, and mild skin symptoms. However, she was not clinically diagnosed. Using whole-exome sequencing, we identified compound heterozygous pathogenic variants in ERCC2. In the future, the patient may develop skin cancer and her neurological symptoms may progress. Early genetic testing is necessary to clarify the cause of symptoms in undiagnosed patients.

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Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency

Yang L., Fujinami K., Ueno S., Kuniyoshi K., Hayashi T., Kondo M., Mizota A., Naoi N., Shinoda K., Kameya S., Fujinami-Yokokawa Y., Liu X., Arno G., Pontikos N., Kominami T., Terasaki H., Sakuramoto H., Katagiri S., Mizobuchi K., Nakamura N., Mawatari G., Kurihara T., Tsubota K., Miyake Y., Yoshitake K., Iwata T., Tsunoda K., Nishimura T., Hayashizaki Y., Shimozawa N., Horiguchi M., Yamamoto S., Kuze M., Machida S., Shimada Y., Nakamura M., Fujikado T., Hotta Y., Takahashi M., Mochizuki K., Murakami A., Kondo H., Ishida S., Nakazawa M., Hatase T., Matsunaga T., Maeda A., Noda K., Tanikawa A., Yamamoto S., Yamamoto H., Araie M., Aihara M., Nakazawa T., Sekiryu T., Kashiwagi K., Kosaki K., Piero C., Fukuchi T., Hayashi A., Hosono K., Mori K., Tanaka K., Furuya K., Suzuki K., Kohata R., Yanagi Y., Minegishi Y., Iejima D., Suga A., Rossmiller B.P., Pan Y., Oshima T., Nakayama M., Yamamoto M., Minematsu N., Mori D., Kijima Y., Kurata K., Yamada N., Itoh M., Kawaji H., Murakawa Y.

Scientific Reports （Scientific Reports） 10 （ 1 ） 2020年12月

© 2020, The Author(s). Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.

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Novel ARX mutation identified in infantile spasm syndrome patient

Takeshita Y., Ohto T., Enokizono T., Tanaka M., Suzuki H., Fukushima H., Uehara T., Takenouchi T., Kosaki K., Takada H.

Human Genome Variation （Human Genome Variation） 7 （ 1 ） 2020年12月

© 2020, The Author(s). We report a 7-year-old boy with infantile spasms caused by a novel mutation in the Aristaless-related homeobox (ARX) gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the ARX gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.

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Cowden syndrome complicated by schizophrenia: A first clinical report

Kobayashi Y., Takeda T., Kunitomi H., Ueki A., Misu K., Kowashi A., Takahashi T., Anko M., Watanabe K., Masuda K., Uchida T., Tominaga E., Banno K., Kosaki K., Aoki D.

European Journal of Medical Genetics （European Journal of Medical Genetics） 63 （ 8 ） 2020年08月

ISSN 17697212

© 2020 Elsevier Masson SAS Patients with Cowden syndrome exhibit mucocutaneous lesions, hamartomatous polyposis of the gastrointestinal tract, and macrocephaly, often complicated by malignant tumors, such as breast, thyroid, and uterine cancers. Autism spectrum and epilepsy have been known as neuropsychiatric symptoms associated with Cowden syndrome; however, to the best of our knowledge, there is no report on cases complicated by schizophrenia. Here, we report a first case of Cowden syndrome complicated by schizophrenia. A 49-year-old Japanese woman started experiencing auditory hallucinations in her teens. She had left breast cancer at the age of 34 years, and right breast cancer at the age of 37 years, all of which were surgically treated. She was also being treated by oral medications for Hashimoto's disease. On consulting her previous doctor for abnormal uterine bleeding that lasted for a year, she was diagnosed with endometrial cancer. However, immediately before surgery, her auditory hallucinations and paranoid delusions became severe, and she was referred to our hospital for detailed examination and treatment. No abnormalities were found on head MRI, and she was diagnosed with schizophrenia on the basis of neuropsychiatric examination findings. After her psychiatric symptoms were controlled by 2 mg of risperidone, she underwent surgery for endometrial cancer. Although there was no apparent family history, physical findings including macrocephaly and papillomatous skin lesions together with her past medical history of multiple malignant tumors suggested Cowden syndrome. Postoperatively, genetic testing revealed a pathogenic variant c.655C > T; p. Gln219* (NM_000314.4) in PTEN, leading to the confirmation of the diagnosis of Cowden syndrome.

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Variant in the neuronal vesicular SNARE VAMP2 (synaptobrevin-2): First report in Japan

Sunaga Y., Muramatsu K., Kosaki K., Sugai K., Mizuno T., Kouno M., Tashiro M.

Brain and Development （Brain and Development） 42 （ 7 ） 529 - 533 2020年08月

ISSN 03877604

© 2020 The Japanese Society of Child Neurology Background: A report presenting five heterozygous de novo variants in VAMP2 in unrelated individuals with a neurodevelopmental disorder characterized by axial hypotonia, intellectual disability, and autistic features was first published in April 4, 2019. Case report: We report the case of a male child with VAMP2 variant who was delivered at 38 weeks and 4 days without neonatal asphyxia. At 4 months of age he showed hypotonia and no visual pursuit and fixation. He presented with infantile spasms at 6 months, and electroencephalography (EEG) showed hypsarrhythmia. His infantile spasms completely disappeared by adrenocorticotropic hormone therapy, but his EEG findings continued to show high voltage slow-waves with multi-focal spikes. At 2 years of age he was non-verbal, had an absence of purposeful hand movements, and no visual fixation. He had somnolence tendency in the daytime. Biochemical and extensive genetic examinations were unrevealed. Magnetic resonance imaging showed slight brain atrophy. At 2 years and 7 months of age, he suffered from myoclonic seizures of the eyelid and tongue, which propagated to unilateral fingers, and sometimes to the bilateral legs. At 8 years of age hyperkinetic movement occurred. At age 13, whole-exome sequence identified a heterozygous missense variant, NM_014232.2:c.199G>C,[p.(Ala67Pro)] in exon 3 of VAMP2 which was a de novo non-synonymous variant. Conclusion: This is the first case report of VAMP2 variant in Japan. Hypotonia at early infancy, poor visual fixation, and absence of purposeful hand movements may be indicative of the diagnosis for VAMP2 variant.

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Consecutive medical exome analysis at a tertiary center: Diagnostic and health-economic outcomes

Kosaki R., Kubota M., Uehara T., Suzuki H., Takenouchi T., Kosaki K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 182 （ 7 ） 1601 - 1607 2020年07月

ISSN 15524825

© 2020 Wiley Periodicals, Inc. The utility of whole exome analysis has been extensively demonstrated in research settings, but its clinical utility as a first-tier genetic test has not been well documented from diagnostic and health economic standpoints in real-life clinical settings. We performed medical exome analyses focusing on a clinically interpretable portion of the genome (4,813 genes) as a first-tier genetic test for 360 consecutive patients visiting a genetics clinic at a tertiary children's hospital in Japan, over a 3-year period. Bioinformatics analyses were conducted using standard software. A molecular diagnosis was made in 171 patients involving a total of 107 causative genes. Among these 107 causative genes, 57 genes were classified as genes with potential organ-specific interventions and management strategies. Clinically relevant results were obtained in 26% of the total cohort and 54% of the patients with a definitive molecular diagnosis. Performing the medical exome analysis at the time of the initial visit to the tertiary center, rather than after visits to pertinent specialists, brain MRI examination, and G-banded chromosome testing, would have reduced the financial cost by 197 euros according to retrospective calculation under multiple assumption. The present study demonstrated a high diagnostic yield (47.5%) for singleton medical exome analysis as a first-tier test in a real-life setting. Medical exome analysis yielded clinically relevant information in a quarter of the total patient cohort. The application of genomic testing during the initial visit to a tertiary medical center could be a rational approach to the diagnosis of patients with suspected genetic disorders.

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Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1

Yamada M., Uehara T., Suzuki H., Takenouchi T., Inui A., Ikemiyagi M., Kamimaki I., Kosaki K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 182 （ 7 ） 1631 - 1636 2020年07月

ISSN 15524825

© 2020 Wiley Periodicals, Inc. Shwachman-Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman-Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183-184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS-specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183-184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood-derived mRNA to demonstrate that the results were compatible with those obtained using SBDS-specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183-184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA-seq is recommended to circumvent this problem.

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Biallelic Mutations in the LSR Gene Cause a Novel Type of Infantile Intrahepatic Cholestasis

Uehara T., Yamada M., Umetsu S., Nittono H., Suzuki H., Fujisawa T., Takenouchi T., Inui A., Kosaki K.

Journal of Pediatrics （Journal of Pediatrics） 221 251 - 254 2020年06月

ISSN 00223476

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Hereditary spastic paraplegia masqueraded by congenital melanocytic nevus syndrome: Dual pathogenesis of germline non-mosaicism and somatic mosaicism

Sakaguchi Y., Uehara T., Sasaki M., Fujimura K., Kishi K., Kosaki K., Takenouchi T.

European Journal of Medical Genetics （European Journal of Medical Genetics） 63 （ 4 ） 2020年04月

ISSN 17697212

© 2019 Elsevier Masson SAS Neurocutaneous disorders are caused by germline and/or somatic mutations and involve the integument and central nervous systems. Congenital melanocytic nevus syndrome is characterized by melanotic skin lesions caused by somatic mutations at codon 61 in NRAS. A large cutaneous lesion raises the risk of central nervous system involvement. We report an 8-year-old girl with a congenital giant pigmented nevus that covered almost her entire back. Despite the absence of any radiological evidence of intracranial melanosis, the patient exhibited progressive limb spasticity with preserved intellectual ability. An extensive genetic analysis identified a specific class of heterozygous germline mutation in SPAST, p.(Arg499His), which is responsible for hereditary spastic paraplegia with infantile onset. In addition, a known heterozygous somatic mutation in NRAS, p.(Gln61Lys) was detected in the cutaneous lesion. This observation recapitulates concomitant mosaicism and non-mosaicism within a single individual and suggests that the possibility of a dual genetic diagnosis should be considered when neurological decline is observed in a patient with a neurocutaneous disorder without any detectable intracranial lesions.

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The Undiagnosed Diseases Network International: Five years and more!

Taruscio D., Baynam G., Cederroth H., Groft S.C., Klee E.W., Kosaki K., Lasko P., Melegh B., Riess O., Salvatore M., Gahl W.A.

Molecular Genetics and Metabolism （Molecular Genetics and Metabolism） 129 （ 4 ） 243 - 254 2020年04月

ISSN 10967192

© 2020 Undiagnosed rare diseases (URDs) account for a significant portion of the overall rare disease burden, depending upon the country. Hence, URDs represent an unmet medical need. A specific challenge posed by the ensemble of the URD patient cohort is the heterogeneity of its composition; the group, indeed, includes very rare, still unidentified conditions as well as clinical variants of recognized rare diseases. Exact disease recognition requires new approaches that cut across national and institutional boundaries, may need the implementation of methods new to diagnostics, and embrace clinical care and research. To address these issues, the Undiagnosed Diseases Network International (UDNI) was established in 2014, with the major aims of providing diagnoses to patients, implementing additional diagnostic tools, and fostering research on novel diseases, their mechanisms, and their pathways. The UDNI involves centres with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis, in particularly for ultra-rare diseases. Consequently, the UDNI fosters the translation of research into medical practice, aided by active patient involvement. The goals of the UDNI are to work collaboratively and at an international scale to: 1) provide diagnoses for individuals who have conditions that have eluded diagnosis by clinical experts; 2) gain insights into the etiology and pathogenesis of novel diseases; 3) contribute to standards of diagnosing unsolved patients; and 4) share the results of UDNI research in a timely manner and as broadly as possible.

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Blended phenotype of AP4E1 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15

Murakami H., Uehara T., Tsurusaki Y., Enomoto Y., Kuroda Y., Aida N., Kosaki K., Kurosawa K.

Brain and Development （Brain and Development） 42 （ 3 ） 289 - 292 2020年03月

ISSN 03877604

© 2020 The Japanese Society of Child Neurology Atypical phenotype of an imprinting disease can develop with a recessive homozygous variant due to uniparental isodisomy. We present a girl with severe intellectual disability, developmental delay, distinctive facial features, and other neuropsychiatric features. Trio whole exome sequencing revealed a novel homozygous frameshift variant in AP4E1 [NM_007347.5:c.2412dupT:p.(Gly805Trpfs*8)] and uniparental isodisomy of chromosome 15 [iUPD(15)]. Single nucleotide polymorphism mapping analysis of exome data showed that the homozygous AP4E1 variant was derived from her heterozygous carrier father and unmasked by paternal iUPD(15). Brain magnetic resonance imaging confirmed the brain abnormalities characteristic of AP4 deficiency including the dilated ventricles and hypointensity in the globus pallidus in susceptibility-weighted imaging. This is the first case report of a combination of AP4E1 deficiency and Angelman syndrome. Our patient indicates that whole exome sequencing could uncover an atypical phenotype caused by multiple genetic factors including the uniparental isodisomy.

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Familial hemiplegic migraine with a PRRT2 mutation: Phenotypic variations and carbamazepine efficacy

Suzuki-Muromoto S., Kosaki R., Kosaki K., Kubota M.

Brain and Development （Brain and Development） 42 （ 3 ） 293 - 297 2020年03月

ISSN 03877604

© 2020 Objective: To understand the clinical characteristics of familial hemiplegic migraine (FHM) caused by a PRRT2 mutation and to examine the efficacy of preventive treatment. Methods: Using the literature, we investigated clinical details of FHM in 3 generations of patients with a PRRT2 mutation and compared them with those in 17 patients with the same mutation from 6 families. Results: In most of the affected patients, the onset was observed during the teen years. Complicated phenotypes tended to be shared in each family, and five patients showed spontaneous remission. With regard to treatment, low-dose carbamazepine (CBZ) was effective in three patients. Conclusion: Considering the clinical features, we suggest that low-dose CBZ is efficacious for FHM treatment in patients with a PRRT2 mutation. The treatment duration should be carefully considered because some patients show spontaneous remission. More accumulated data from familial cases might help elucidate PRRT2 function and establish standard treatment for FHM.

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Mexiletine shortens the QT interval in a pedigree of KCNH2 related long QT syndrome

Fujisawa T., Aizawa Y., Katsumata Y., Kimura K., Hashimoto K., Yamashita T., Miyama H., Kimura T., Kosaki K., Takatsuki S., Shimizu W., Fukuda K.

Journal of Arrhythmia （Journal of Arrhythmia） 36 （ 1 ） 193 - 196 2020年02月

ISSN 18804276

© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society. A 23-year-old female had been suffering from recurrent syncopal episodes during sleep since her childhood. She had a family history of sudden death and her QTc interval was remarkably prolonged to 537 ms A Holter ECG revealed torsade de pointes, corresponding to syncope. She was started on mexiletine and her QTc interval shortened. Her symptoms were controlled after β-blockers and Ca-blockers were added. A genetic analysis with a next generation sequencer identified a frameshift mutation at the C terminus of the KCNH2 gene. Here we present a type 2 long QT syndrome case in which mexiletine was effective.

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Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

Hiraide T., Kataoka M., Suzuki H., Aimi Y., Chiba T., Isobe S., Katsumata Y., Goto S., Kanekura K., Yamada Y., Moriyama H., Kitakata H., Endo J., Yuasa S., Arai Y., Hirose N., Satoh T., Hakamata Y., Sano M., Gamou S., Kosaki K., Fukuda K.

Journal of Heart and Lung Transplantation （Journal of Heart and Lung Transplantation） 39 （ 2 ） 103 - 112 2020年02月

ISSN 10532498

© 2019 International Society for Heart and Lung Transplantation BACKGROUND: A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. METHODS: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. RESULTS: The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs 93%, respectively; p < 0.001). CONCLUSIONS: Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.

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Improvement of opsoclonus after congenital cataract surgery in an infant

Yamaguchi H., Morisada N., Maruyama A., Kosaki K., Nomura K.

Pediatrics International （Pediatrics International） 62 （ 1 ） 108 - 109 2020年01月

ISSN 13288067

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Infantile neuroaxonal dystrophy in a pair of Malaysian siblings with progressive cerebellar atrophy: Description of an expanded phenotype with novel PLA2G6 variants

Li L., Fong C.Y., Tay C.G., Tae S.K., Suzuki H., Kosaki K., Thong M.K.

Journal of Clinical Neuroscience （Journal of Clinical Neuroscience） 71 289 - 292 2020年01月

ISSN 09675868

© 2019 Elsevier Ltd Infantile neuroaxonal dystrophy 1 (INAD) (OMIM #256600) is a rare infantile onset neurodegenerative disease characterised by neuroregression and hypotonia, evolving into generalized spasticity, blindness and dementia. We report our diagnostic approach of a pair of siblings with psychomotor regression, hypotonia, optic atrophy and auditory neuropathy. The brain magnetic resonance imaging (MRI) showed progressive cerebellar atrophy. Genetic testing of the PLA2G6 confirmed presence of compound heterozygous novel mutations. As the variant c. 196C>T (p.Gln66X) was a truncating variant, it was considered as pathogenic while the variant c. 2249G>A (p. Cys750Tyr) was considered as “likely pathogenic” by bioinformatics analyses. Our patient expands the clinical phenotype of INAD as it described the first South-East Asian patient with INAD-associated auditory neuropathy. Our report highlights the importance of increased awareness of this condition amongst clinicians, the use of deep phenotyping using neuroimaging and the clinical utility of gene sequencing test in the delineation of syndromes associated with infantile neurodegenerative disease.

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Diagnostic utility of integrated analysis of exome and transcriptome: Successful diagnosis of Au-Kline syndrome in a patient with submucous cleft palate, scaphocephaly, and intellectual disabilities

Yamada M., Shiraishi Y., Uehara T., Suzuki H., Takenouchi T., Abe-Hatano C., Kurosawa K., Kosaki K.

Molecular Genetics and Genomic Medicine （Molecular Genetics and Genomic Medicine） 2020年

© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC Background: A weakness of exome analysis lies in inability to characterize aberrant splicing other than those involving consensus donor-acceptor sequence. To overcome this limitation, we developed a novel analytic method SAVNet that combines transcriptome and exome analysis which enabled the successful detection of carriers of splicing variants in the disease-causing genes of autosomal recessive disorders within a normal cohort. However, the clinical utility of the SAVNet analysis in delineating splicing defects in patients without a diagnosis has yet to be documented. Method: We performed SAVNet analysis using the integrated analysis of exome and transcriptome analysis from the peripheral blood of the patient. The patient is an undiagnosed Japanese female patient with submucous cleft palate, scaphocephaly and intellectual disability with no words at 8 years of age. Dysmorphic features included a long face, a short palpebral fissure, thick lips with an open month, premaxillary hypoplasia, a depressed nasal bridge, and satyr ears. Result: A SAVNet analysis showed that a heterozygous intronic variant located at the −10 position of exon 5 of the HNRNPK gene on chromosome 9 created a new splice acceptor sequence “ag” and led to the incorporation of 9 intronic nucleotides into the coding sequence. The mutant protein would have three extra amino acid residues, Leu-Leu-Gln, inserted within the critical KH domain. The patient was diagnosed as having recently delineated Au–Kline syndrome, which is characterized by cleft palate, craniosynostosis, and intellectual disability. Conclusion: The successful molecular diagnosis of the presently reported patient illustrates the diagnostic utility of the SAVNet analysis as an innovative way of implementing an integrated exome-transcriptome analysis in clinical settings.

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BioHackathon 2015: Semantics of data for life sciences and reproducible research

Katayama T., Vos R.A., Mishima H., Kawano S., Kawashima S., Kim J.D., Moriya Y., Tokimatsu T., Yamaguchi A., Yamamoto Y., Wu H., Amstutz P., Antezana E., Aoki N.P., Arakawa K., Bolleman J.T., Bolton E., Bonnal R.J.P., Bono H., Burger K., Chiba H., Cohen K.B., Deutsch E.W., Fernández-Breis J.T., Fu G., Fujisawa T., Fukushima A., García A., Goto N., Groza T., Hercus C., Hoehndorf R., Itaya K., Juty N., Kawashima T., Kim J.H., Kinjo A.R., Kotera M., Kozaki K., Kumagai S., Kushida T., Lütteke T., Matsubara M., Miyamoto J., Mohsen A., Mori H., Naito Y., Nakazato T., Nguyen-Xuan J., Nishida K., Nishida N., Nishide H., Ogishima S., Ohta T., Okuda S., Paten B., Perret J.L., Prathipati P., Prins P., Queralt-Rosinach N., Shinmachi D., Suzuki S., Tabata T., Takatsuki T., Taylor K., Thompson M., Uchiyama I., Vieira B., Wei C.H., Wilkinson M., Yamada I., Yamanaka R., Yoshitake K., Yoshizawa A.C., Dumontier M., Kosaki K., Takagi T.

F1000Research （F1000Research） 9 2020年

ISSN 20461402

© 2020 Vos RA et al. We report on the activities of the 2015 edition of the BioHackathon, an annual event that brings together researchers and developers from around the world to develop tools and technologies that promote the reusability of biological data. We discuss issues surrounding the representation, publication, integration, mining and reuse of biological data and metadata across a wide range of biomedical data types of relevance for the life sciences, including chemistry, genotypes and phenotypes, orthology and phylogeny, proteomics, genomics, glycomics, and metabolomics. We describe our progress to address ongoing challenges to the reusability and reproducibility of research results, and identify outstanding issues that continue to impede the progress of bioinformatics research. We share our perspective on the state of the art, continued challenges, and goals for future research and development for the life sciences Semantic Web.

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A case of generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement with short and long-term monitoring of the metabolic and endocrine profiles

Fukaishi T., Minami I., Masuda S., Miyachi Y., Tsujimoto K., Izumiyama H., Hashimoto K., Yoshida M., Takahashi S., Kashimada K., Morio T., Kosaki K., Maezawa Y., Yokote K., Yoshimoto T., Yamada T.

Endocrine Journal （Endocrine Journal） 67 （ 2 ） 211 - 218 2020年

ISSN 09188959

© The Japan Endocrine Society. We herein report a case of a 28-year-old man with generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement. He showed symptoms of generalized lipodystrophy around onset of puberty. His body mass index was 11.9 kg/m2, and he had a short stature, birdlike facies, dental crowding due to micrognathia, partial graying and loss of hair, and a high-pitched voice, all of which are typical features of the progeroid syndrome. Laboratory examinations and abdominal ultrasonography revealed diabetes mellitus, insulin-resistance, dyslipidemia, decreased serum leptin levels (2.2 ng/ mL), elevated serum hepatobiliary enzyme levels and fatty liver. Whole exome sequencing revealed de novo heterozygous LMNA p.T10I mutation, indicating generalized lipodystrophy-associated progeroid syndrome, which is a newly identified subtype of atypical progeroid syndrome characterized by severe metabolic abnormalities. Daily injection of metreleptin [1.2 mg (0.04 mg/kg)/day] was started. Metreleptin treatment significantly improved his diabetes from HbA1c 11.0% to 5.4% in six months. It also elevated serum testosterone levels. Elevated serum testosterone levels persisted even 1 year after the initiation of metreleptin treatment. To the best of our knowledge, this is the first Japanese case report of generalized lipodystrophy-associated progeroid syndrome. Furthermore, we evaluated short and long-term effectiveness of leptin replacement on generalized lipodystrophy by monitoring metabolic and endocrine profiles.

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Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta

Takenouchi T., Okuno H., Kosaki K.

American Journal of Medical Genetics, Part C: Seminars in Medical Genetics （American Journal of Medical Genetics, Part C: Seminars in Medical Genetics） 181 （ 4 ） 650 - 657 2019年12月

ISSN 15524868

© 2019 Wiley Periodicals, Inc. Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

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MGeND: an integrated database for Japanese clinical and genomic information

Kamada M., Nakatsui M., Kojima R., Nohara S., Uchino E., Tanishima S., Sugiyama M., Kosaki K., Tokunaga K., Mizokami M., Okuno Y.

Human Genome Variation （Human Genome Variation） 6 （ 1 ） 2019年12月

© 2019, The Author(s). To promote the implementation of genomic medicine, we developed an integrated database, the Medical Genomics Japan Variant Database (MGeND). In its first release, MGeND provides data regarding genomic variations in Japanese individuals, collected by research groups in five disease fields. These variations consist of curated SNV/INDEL variants and susceptibility variants for diseases established by genome-wide association study analysis. Furthermore, we recorded the frequencies of HLA alleles in infectious disease populations.

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Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

Kubo A., Sasaki T., Suzuki H., Shiohama A., Aoki S., Sato S., Fujita H., Ono N., Umegaki-Arao N., Kawai T., Nakabayashi K., Hata K., Yamada D., Matsubara Y., Kosaki K., Amagai M.

Journal of Investigative Dermatology （Journal of Investigative Dermatology） 139 （ 12 ） 2458 - 2466.e9 2019年12月

ISSN 0022202X

© 2019 The Authors Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as MVD or MVK. Here, we showed that each skin lesion of DSAP exhibited an individual second hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. Most skin lesions exhibited one of two principal second hits, either somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele. The second hits differed among DSAP lesions but were identical in those of congenital LP, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital LP to a single second hit in the embryonic period. In the characteristic annular skin lesions of DSAP, the central epidermis featured mostly second hit keratinocytes, and that of the annular ring featured a mixture of such cells and naïve keratinocytes, implying that each lesion reflects the clonal expansion of single second hit keratinocytes. DSAP is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson's two-hit hypothesis.

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Effectiveness of integrated interpretation of exome and corresponding transcriptome data for detecting splicing variants of genes associated with autosomal recessive disorders

Yamada M., Suzuki H., Shiraishi Y., Kosaki K.

Molecular Genetics and Metabolism Reports （Molecular Genetics and Metabolism Reports） 21 2019年12月

© 2019 The Authors Purpose: Part of the weakness of exome analysis lies in the inability to detect aberrant splicing. An evaluation of the post-splicing mRNA sequence concurrently with genomic variants could improve the diagnostic rate. We aimed to investigate publicly available exome sequencing data and its matching transcriptomics data of phenotypically normal individuals to identify alternatively spliced variants from known genes associated with autosomal recessive disorders under the premise that some of the subjects could be carriers of such disorders. Methods: Aberrant splicing events and their triggering genomic variants were detected with the aid of Bayesian network method “SAVNet” which was originally developed for cancer genomics. Results: Forty aberrant splicing events including exon skipping, the creation of a new splice site, and the use of a cryptic splice site in response to the disruption of the authentic site were detected in 1916 genes among 31 of the 179 subjects from the 1000 Genomes Project. The predicted effects on proteins were either frameshift mutations (30) or large in-frame insertions or deletions (10). Five missense mutations and 2 silent mutations were reinterpreted as triggering major changes in transcript sequences. The detection rate of provisionally truncating pathogenic variants increased by 19%, compared with a conventional exome analysis. Conclusion: The coupling interpretation of exome and transcriptome data enhances the performance of conventional exome analyses through the proper interpretation of intronic variants that are outside of the GT/AG splicing consensus sequences and also allows the reinterpretation of “missense” or “silent” substitutions that can indeed have drastic effects on splicing.

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A case of autism spectrum disorder with cleft lip and palate carrying a mutation in exon 8 of AUTS2

Saeki S., Enokizono T., Imagawa K., Fukushima H., Kajikawa D., Sakai A., Tanaka M., Ohto T., Suzuki H., Uehara T., Takenouchi T., Kenjiro K., Takada H.

Clinical Case Reports （Clinical Case Reports） 7 （ 11 ） 2059 - 2063 2019年11月

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De novo NSF mutations cause early infantile epileptic encephalopathy

Suzuki H., Yoshida T., Morisada N., Uehara T., Kosaki K., Sato K., Matsubara K., Takano-Shimizu T., Takenouchi T.

Annals of Clinical and Translational Neurology （Annals of Clinical and Translational Neurology） 6 （ 11 ） 2334 - 2339 2019年11月

© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. N-ethylmaleimide-sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild-type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy.

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Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers

Suzuki H., Takenouchi T., Uehara T., Takasago S., Ihara S., Yoshihashi H., Kosaki K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 179 （ 8 ） 1628 - 1630 2019年08月

ISSN 15524825

© 2019 Wiley Periodicals, Inc. Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.

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Establishment of immunity against Epstein-Barr virus infection in a patient with CHARGE/complete DiGeorge syndrome after peripheral blood lymphocyte transfusion

Hosaka S., Kobayashi C., Saito H., Imai-Saito A., Suzuki R., Iwabuchi A., Kato Y., Jimbo T., Watanabe N., Onodera M., Imadome K., Masumoto K., Nanmoku T., Fukushima T., Kosaki K., Sumazaki R., Takada H.

Pediatric Transplantation （Pediatric Transplantation） 23 （ 4 ） e13424 2019年06月

ISSN 13973142

© 2019 Wiley Periodicals, Inc. CHARGE syndrome is a rare congenital malformation syndrome which may share symptoms with DiGeorge syndrome. Complete DiGeorge syndrome (cDGS) is a severe form of DiGeorge syndrome, characterized by a CD3+ T-cell count of <50/mm 3 due to athymia, and is fatal without immunologic intervention. We performed peripheral blood lymphocyte transfusion (PBLT) from an HLA-identical sibling without pretransplant conditioning in a CHARGE/cDGS patient with a novel CHD7 splice site mutation. Cyclosporine and short-term methotrexate were used for graft versus host disease (GVHD) prophylaxis, and neither acute nor chronic GVHD was observed. After PBLT, T-cell proliferative response to phytohemagglutinin and concanavalin A recovered, and intractable diarrhea improved. EBV infection, evidenced by a gradual increase in the viral genome copy number to a maximum of 2861 copies/μgDNA on day 42 after PBLT, resolved spontaneously. HLA A2402 restricted, EBV-specific CTLs were detected from peripheral blood on day 148, and EBV seroconversion was observed on day 181. Thus, EBV-specific immunity was successfully established by PBLT. Our results indicate that PBLT is a simple and effective therapy to reconstitute immune systems in CHARGE/DiGeorge syndrome.

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SATB2-associated syndrome in patients from Japan: Linguistic profiles

Yamada M., Uehara T., Suzuki H., Takenouchi T., Yoshihashi H., Suzumura H., Mizuno S., Kosaki K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 179 （ 6 ） 896 - 899 2019年06月

ISSN 15524825

© 2019 Wiley Periodicals, Inc. Cleft palate can be classified as either syndromic or nonsyndromic. SATB2-associated syndrome is one example of a syndromic cleft palate that is accompanied by intellectual disability, and various dental anomalies. SATB2-associated syndrome can be caused by several different molecular mechanisms including intragenic mutations and deletions of SATB2. Here, we report two patients with SATB2 truncating mutations (p.Arg239* and p.Asp702Thrfs*38) and one with a 4.4 megabase deletion including the SATB2 locus. All three patients had cleft palate and other dysmorphic features including macrodontia wide diastema. None of the three patients had acquired any meaningful words at the age of 5 years. In a review of the linguistic natural history of presently reported three patients and 30 previously reported patients, only two patients had attained verbal skills beyond speaking a few words. This degree of delayed speech contrasts with that observed in the prototypic form of syndromic cleft palate, 22q11.2 deletion syndrome. The recognition of SATB2-associated syndrome prior to palatoplasty would be important for plastic surgeons and the families of patients because precise diagnosis should provide predictive information regarding the future linguistic and intellectual abilities of the patients. Macrodontia with a wide diastema and cleft palate is a helpful and highly suggestive sign for the diagnosis of SATB2-associated syndrome.

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Sweat Retention Anhidrosis Associated with Tubular Aggregate Myopathy.

Ishitsuka Y, Inoue S, Furuta JI, Koguchi-Yoshioka H, Nakamura Y, Watanabe R, Okiyama N, Fujisawa Y, Enokizono T, Hiroko F, Suzuki H, Nishino I, Kosaki K, Fujimoto M.

Br J Dermatol. 2019年05月

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Evaluation of Face2Gene using facial images of patients with congenital dysmorphic syndromes recruited in Japan.

Mishima H, Suzuki H, Doi M, Miyazaki M, Watanabe S, Matsumoto T, Morifuji K, Moriuchi H, Yoshiura KI, Kondoh T, Kosaki K.

J Hum Genet. （J Hum Genet.） 2019年05月

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A novel missense PTEN mutation identified in a patient with macrocephaly and developmental delay.

Ueno Y, Enokizono T, Fukushima H, Ohto T, Imagawa K, Tanaka M, Sakai A, Suzuki H, Uehara T, Takenouchi T, Kosaki K, Takada H.

Hum Genome Var. 2019年05月

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Noninvasive diagnosis of TRIT1-related mitochondrial disorder by measuring i6A37 and ms2i6A37 modifications in tRNAs from blood and urine samples

Takenouchi T., Wei F., Suzuki H., Uehara T., Takahashi T., Okazaki Y., Kosaki K., Tomizawa K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 2019年05月

ISSN 15524825

© 2019 Wiley Periodicals, Inc. Subsets of mitochondrial transfer RNA (tRNA) contain the N6-isopentenyladenosine (i6A) or 2-methylthio-N6-isopentenyladenosine (ms2i6A) modification at position A37, which is adjacent to an anticodon. These modifications are essential for efficient protein translation in mitochondria and contribute to energy metabolism. The first step in i6A and ms2i6A modifications is catalyzed by tRNA isopentenyltransferase, which is encoded by the TRIT1 gene. Herein, we report a girl with a developmental delay, frequent episodes of seizures induced by febrile illness, and myoclonic epilepsy who had compound heterozygous missense mutations in TRIT1. A mass spectrometry analysis of RNA nucleoside obtained from the subject's peripheral blood and urine showed a marked decrease in both i6A and ms2i6A modifications. These results suggest that the mitochondrial disorder was caused by defective tRNA isopentenylation arising from a loss-of-function mutation in TRIT1. Furthermore, the present observations suggest that noninvasive biochemical analysis using peripheral blood and urine samples are sufficient for the diagnosis of TRIT1-related disorders, making muscle biopsy for the direct measurement of oxidative phosphorylation unnecessary. Such biochemical analyses before the start of antiepileptic medications would be beneficial to avoid hepatotoxicity in patients with possible mitochondrial disorders.

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CNOT2 as the critical gene for phenotypes of 12q15 microdeletion syndrome

Uehara T., Takenouchi T., Yamaguchi Y., Daimon Y., Suzuki H., Sakaguchi Y., Kosaki K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 179 （ 4 ） 659 - 662 2019年04月

ISSN 15524825

© 2019 Wiley Periodicals, Inc. Chromosome 12q15 microdeletion syndrome is characterized by intellectual disability and dysmorphic facial features, but the associations between each of the deleted genes and the phenotypes of 12q15 microdeletion syndrome remain unclear. Recently, the smallest region of overlap in 16 previously reported patients was used to define three candidate genes for the 12q15 microdeletion syndrome: CNOT2, KCNMB4, and PTPRB. Among these three candidate genes, CNOT2 maintains the structural integrity of the carbon catabolite repressor 4 (CCR4)-negative on TATA (NOT) complex, which plays a key role in regulating global gene expression, and is essential for the enzymatic activity of the CCR4-NOT complex. Disruption of the CCR4-NOT complex results in dysregulation of global gene expression, and is associated with various human disease processes, including neuronal diseases. Therefore, CNOT2 haploinsufficiency might account for the neurological features of the 12q15 microdeletion syndrome. Herein, we document a 12-year-old female patient with mild intellectual disability and multiple structural abnormalities including cleft lip and palate and 2–3 toe syndactyly. She exhibited dysmorphic facial features such as upslanting and short palpebral fissures, micrognathia, low-set ears, and hypoplastic antihelix. A microarray analysis showed a de novo 1.32-Mb deletion within 12q15 that included CNOT2 and 14 other genes. Remapping of the 12q15 deletion region in the 16 previously reported patients together with that in the newly identified patient indicated that CNOT2 is the only gene that is commonly deleted. These findings suggest that CNOT2 is the prime candidate for the neurological phenotypes of the 12q15 microdeletion syndrome.

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Pathogenetic basis of Takenouchi-Kosaki syndrome: Electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model

Uehara T., Suzuki H., Okamoto N., Kondoh T., Ahmad A., O’Connor B., Yoshina S., Mitani S., Kosaki K., Takenouchi T.

Scientific Reports （Scientific Reports） 9 （ 1 ） 2019年03月

© 2019, The Author(s). The combined phenotype of thrombocytopenia accompanied by intellectual disability in patients with a de novo heterozygous mutation, i.e., p.Tyr64Cys in CDC42, signifies a clinically recognizable novel syndrome that has been eponymized as “Takenouchi-Kosaki syndrome” (OMIM #616737). In the present study, a detailed phenotypic analysis performed for a total of five patients with Takenouchi-Kosaki syndrome revealed that intellectual disability, macrothrombocytopenia, camptodactyly, structural brain abnormalities with sensorineural deafness, hypothyroidism, and frequent infections comprise the cardinal features of this condition. A morphologic analysis of platelets derived from three affected individuals was performed using electron microscopy. The platelets of the three patients were large and spherical in shape. Furthermore, platelet α-granules were decreased, while vacuoles were increased. We further performed a functional analysis of p.Tyr64Cys in CDC42 through CRISPR/Cas9-mediated gene editing in a Caenorhabditis elegans model. This functional analysis suggested that the mutant allele has hypomorphic effects. Takenouchi-Kosaki syndrome is clinically recognizable by the combined phenotype of intellectual disability, macrothrombocytopenia, camptodactyly, structural brain abnormalities with sensorineural deafness, hypothyroidism, and frequent infections as well as the identification of a heterozygous de novo mutation in CDC42, i.e., p.Tyr64Cys.

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Schuurs-Hoeijmakers syndrome in two patients from Japan

Hoshino Y., Enokizono T., Imagawa K., Tanaka R., Suzuki H., Fukushima H., Arai J., Sumazaki R., Uehara T., Takenouchi T., Kosaki K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 179 （ 3 ） 341 - 343 2019年03月

ISSN 15524825

© 2018 Wiley Periodicals, Inc. Schuurs-Hoeijmakers syndrome is a rare disease characterized by intellectual disability and dysmorphic facial features among various physical abnormalities due to PACS1 mutation. To date, 28 patients with a recurrent de novo PACS1 mutation (c.607C > T) have been reported, primarily in Western populations. Here, we describe two Japanese patients with Schuurs-Hoeijmakers syndrome with a recurrent PACS1 mutation. In addition to the typical clinical symptoms, each patient presented novel clinical phenotypes. One patient presented with involuntary movements and was treated with trihexyphenidyl hydrochloride. We hypothesized that the PACS1 mutation leads to an inherent dopaminergic insufficiency that underlies the developing symptoms along with the neurodevelopmental processes. The second patient was diagnosed with lipomyelomeningocele during an examination for severe constipation at the age of 2 years and 8 months. The diagnosis of lipomyelomeningocele in this patient was delayed due to the lack of cutaneous lesions. As the majority of patients with PACS1 mutation present constipation, underdiagnosis of lipomyelomeningocele is a possibility. As the phenotypic expansion of the patients with Schuurs-Hoeijmakers syndrome was not fully recognized, additional studies are needed to clarify the clinical spectrum.

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Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare

Yasuda J., Kinoshita K., Katsuoka F., Danjoh I., Sakurai-Yageta M., Motoike I., Kuroki Y., Saito S., Kojima K., Shirota M., Saigusa D., Otsuki A., Kawashima J., Yamaguchi-Kabata Y., Tadaka S., Aoki Y., Mimori T., Kumada K., Inoue J., Makino S., Kuriki M., Fuse N., Koshiba S., Tanabe O., Nagasaki M., Tamiya G., Shimizu R., Takai-Igarashi T., Ogishima S., Hozawa A., Kuriyama S., Sugawara J., Tsuboi A., Kiyomoto H., Ishii T., Tomita H., Minegishi N., Suzuki Y., Suzuki K., Kawame H., Tanaka H., Taki Y., Yaegashi N., Kure S., Nagami F., Kosaki K., Sutoh Y., Hachiya T., Shimizu A., Sasaki M., Yamamoto M.

Journal of Biochemistry （Journal of Biochemistry） 165 （ 2 ） 139 - 158 2019年02月

ISSN 0021924X

© The Author(s) 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.

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A Homozygous CASQ2 Mutation in a Japanese Patient with Catecholaminergic Polymorphic Ventricular Tachycardia.

Fujisawa T, Aizawa Y, Katsumata Y, Udo A, Ito S, Hatakeyama K, Hirose M, Miyama H, Nakajima K, Nishiyama T, Kimura T, Nitta M, Misumi K, Takatsuki S, Kosaki K, Fukuda K.

Case Rep Genet （Case Rep Genet） 2019年01月

共著

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Medical genetics and genomic medicine in Japan

Suzuki H., Watanabe T., Uehara T., Kosaki K.

American Journal of Medical Genetics, Part C: Seminars in Medical Genetics （American Journal of Medical Genetics, Part C: Seminars in Medical Genetics） 2019年

ISSN 15524868

© 2019 Wiley Periodicals, Inc. Since 1961, all Japanese citizens have belonged to one of the available medical care insurance systems. This “universal care” system has contributed to the maintenance of health: the life expectancy at birth was 84 years in 2016, and the infant mortality rate (the number of infants dying before reaching 1 year of age) was 2.0 per 1,000 live births, which is one of the lowest rates in the world. The Japanese government initiated the National Program on Rare and Intractable Diseases in 1972. This program has promoted research and expanded support for patients with rare and intractable diseases. Registered patients are eligible for a subsidy scheme that helps to cover medical care costs. Among the 331 diseases that are currently included in this program, more than half of the diseases are Mendelian disorders. The National Program on Rare and Intractable Diseases has fostered research in medical genetics in Japan and many causative genes for Mendelian diseases have been identified by Japanese geneticists. Recently, the Japanese government has determined to support several genomic medicine initiatives including the undiagnosed disease program (Initiative on Rare and Undiagnosed Diseases) and pathogenic variant databases.

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Refractory epilepsy and regression in a patient with a de novo heterozygous POGZ mutation

Yamagata S., Hattori A., Miya F., Kubota Y., Endo T., Negishi Y., Nakamura Y., Tsunoda T., Kosaki K., Saitoh S.

No To Hattatsu （No To Hattatsu） 51 （ 1 ） 29 - 32 2019年

ISSN 00290831

© 2019 Japanese Society of Child Neurology. All Rights Reserved. Mutations in the pogo transposable element with zinc finger domain（POGZ）gene are associated with autism spectrum disorder （ASD）and intellectual disability. A total of 40 cases have been reported, and their clinical features include severe phenotypes such as severe speech and language delay, vision problems, microcephaly, and a predisposition towards obesity. Although 20% of these cases showed EEG abnormalities, epilepsy has not been reported. We present the case of a patient with refractory epilepsy and regression in which whole exome sequencing identified a de novo heterozygous POGZ mutation（c.2102del;p.Pro701Leufs ＊ 18）. He was diagnosed with autism spectrum disorder at 6 years of age. From 7 years and 8 months of age, he experienced epileptic seizures that involved falling backwards, head nodding and ocular deviation. An EEG showed a spike-and-slow-wave at F3 and F4. He was diagnosed with frontal lobe epilepsy, and treated with various anti-epileptic drugs （e.g. CZP, VPA, CLB, PHT, LTG, PB, CBZ and LEV）, which eventually reduced his epileptic seizures from over 10 to 2-3 times per day. Moreover, this patient had repetitive aspiration pneumonia from 14 years of age, necessitating a tracheotomy and laryngo-tracheal separation. Phenotypes associated with a POGZ mutation might, therefore, have a wider spectrum than previously recognized, and include not only ASD, but various neurological problems such as progressive epilepsy syndrome.

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Acromegaly caused by a somatotroph adenoma in patient with neurofibromatosis type 1

Hozumi K., Fukuoka H., Odake Y., Takeuchi T., Uehara T., Sato T., Inoshita N., Yoshida K., Matsumoto R., Bando H., Hirota Y., Iguchi G., Taniguchi M., Otsuki N., Nishigori C., Kosaki K., Hasegawa T., Ogawa W., Takahashi Y.

Endocrine Journal （Endocrine Journal） 66 （ 10 ） 853 - 857 2019年

ISSN 09188959

© The Japan Endocrine Society. Although acromegaly has been reported in patients with Neurofibromatosis type 1 (NF1), these cases have not been associated with growth hormone (GH)-producing somatotroph adenoma, but with optic pathway glioma. A 68 year-old Japanese woman, who had been clinically diagnosed with NF1, was referred to our hospital due to a thyroid tumor and hypercalcemia. Acromegaly was suspected due to her facial features, and subsequent examinations revealed the presence of GH excess with a pituitary tumor, leading to the diagnosis of acromegaly. Histological and immunohistochemical analysis demonstrated an eosinophilic pituitary adenoma with diffuse positivity for GH, indicating typical somatotroph adenoma. In addition, her thyroid tumor was diagnosed histologically as follicular thyroid carcinoma (FTC) with primary hyperparathyroidism (PHPT). To investigate the pathogenesis of this untypical multiple endocrine tumor case of NF1, genetic analysis was performed using peripheral leukocytes and tissue of resected tumors. A heterozygous novel germline nonsense mutation (p.Arg1534*) in exon 35 of the NF1 gene was detected from peripheral leukocytes, which results in a truncated protein lacking the critical domain for GTPase activity, strongly suggesting its causal role in NF1. The loss of heterozygosity (LOH) in exon 35 of the NF1 gene was not detected in the somatotroph adenoma, parathyroid adenoma, and FTC. Although any mutations of the following genes; MEN1, CDKN1B, and PAX8-PPAR? were not detected, a heterozygous GNAS R201C mutation was detected in the somatotroph adenoma. To our knowledge, this is the first rare MEN1-like case of genetically diagnosed NF1 complicated with acromegaly caused by a somatotroph adenoma.

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A case of familial episodic pain syndrome with SCN11A mutation treated prophylactically with sodium channel blockers

Tanaka F., Goto T., Ogawa E., Moriyama S., Ito A., Kurosawa K., Kosaki K.

No To Hattatsu （No To Hattatsu） 51 （ 4 ） 266 - 270 2019年

ISSN 00290831

© 2019 Japanese Society of Child Neurology. All rights reserved. Familial episodic pain disorder is a rare autosomal-dominant disorder characterized by recurrent attacks of pain. A gain-of-function mutation in SCN11A has been identified in this rare, early-onset familial episodic pain disorder. Currently available treatment options are warmth, massage, and administration of analgesics. Here, we report a patient with familial episodic pain disorder who received prophylactic treatment. A 4-year old Japanese girl presented with a history of intense episodic pain in the distal extremities and knees since infancy. Pain attacks were sometimes triggered by low ambient temperatures or fatigue, although the trigger for the majority of attacks could not be identified. She experienced frequent episodes of pain (5 or 6 attacks per day) with each attack lasting 30-60 min. Each attack persisted for 2 or 3 days and occurred every week. The pain was intense and unbearable, occurring late in the day or at night. The patient sometimes awoke from sleep because of the pain. There was no change in skin color, nor did she experience sweating during pain attacks. Her 32-year-old father has been experiencing the same symptoms since childhood. Investigation of the family history revealed many affected individuals with the autosomal-dominant trait. The severity of pain in the affected family members decreased with age. The patient's father continues to take analgesics ones or twice a month. An SCN11A mutation, NM-014139.2: c. 665 G>A(p.Arg222His), was identified in the family. Acetaminophen was effective, but the patient required frequent administration; therefore, we considered prophylactic treatment. Carbamazepine and gabapentin did not yield adequate relief. Subsequently, we administered lamotrigine, which was reportedly effective in a previous case of the p. Arg222His mutation. However, lamotrigine was ineffective for our patient. Currently, no prophylactic treatment has been identified that consistently prevents pain attacks in familial episodic pain disorder.

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Mutations of RAS genes in endometrial polyps

Takeda T., Banno K., Kobayashi Y., Adachi M., Yanokura M., Tominaga E., Kosaki K., Aoki D.

Oncology Reports （Oncology Reports） 42 （ 6 ） 2303 - 2308 2019年

ISSN 1021335X

© 2019 Spandidos Publications. All rights reserved. Endometrial polyps are common, yet the molecular mechanisms underlying their formation and progression remain unclear. We examined gene mutations possibly related to the pathogenesis of endometrial polyps, as well as to their clinical features. Four premenopausal patients with endometrial polyps, who were not under drug treatment, were recruited. Whole exomes of endometrial polyps and peripheral blood lymphocytes were analyzed by next-generation sequencing, and somatic mutations were derived by subtraction. Then, 35 samples of endometrial polyps and 12 samples of atypical polypoid adenomyoma were newly recruited to validate the identified mutations by polymerase chain reaction-reverse sequence specific oligonucleotide method. The mutations were also analyzed in separate stromal and glandular components of the polyps after laser-capture microdissection. Whole exome sequencing revealed that KRASmutations were the only type of mutation detectable in multiple cases (2/4). Targeted mutation analysis revealed that 16 of 35 samples (45.7%) of endometrial polyps harbored RAS mutations. Mutation-positive cases exhibited a significantly higher number of endometrial polyps (3.25±2.70 vs. 1.74±0.87, P=0.045). Laser-capture microdissection in NRAS-mutated endometrial polyps revealed that both stromal and glandular components harbored RAS mutations. There was no RAS mutation in 12 samples of atypical polypoid adenomyoma. This is the first report demonstrating that pathogenic RAS mutations are frequent in non-treated endometrial polyps. RAS mutations may have an important role in tumorigenesis and in the formation of multiple endometrial polyps.

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Phenotypical characteristics of POC1B-associated retinopathy in Japanese cohort: Cone dystrophy with normal funduscopic appearance

Kameya S., Fujinami K., Ueno S., Hayashi T., Kuniyoshi K., Ideta R., Kikuchi S., Kubota D., Yoshitake K., Katagiri S., Sakuramoto H., Kominami T., Terasaki H., Yang L., Fujinami-Yokokawa Y., Liu X., Arno G., Pontikos N., Miyake Y., Iwata T., Tsunoda K., Mizota A., Shinoda K., Nakamura N., Mizobuchi K., Nishimura T., Hayashizaki Y., Kondo M., Shimozawa N., Horiguchi M., Yamamoto S., Kuze M., Naoi N., Machida S., Shimada Y., Nakamura M., Fujikado T., Yoshihiro H., Takahashi M., Mochizuki K., Murakami A., Kondo H., Ishida S., Nakazawa M., Hatase T., Matsunaga T., Maeda A., Noda K., Tanikawa A., Yamamoto S., Yamamoto H., Araie M., Aihara M., Nakazawa T., Sekiryu T., Kashiwagi K., Kosaki K., Piero C., Fukuchi T., Hayashi A., Hosono K., Mori K., Tanaka K., Furuya K., Suzuki K., Kohata R., Yanagi Y., Minegishi Y., Iejima D., Suga A., Rossmiller B.P., Pan Y., Oshima T., Nakayama M., Yamamoto M., Minematsu N., Mori D., Kijima Y., Mawatari G., Kurata K., Yamada N., Itoh M., Kawaji H., Murakawa Y.

Investigative Ophthalmology and Visual Science （Investigative Ophthalmology and Visual Science） 60 （ 10 ） 3432 - 3446 2019年

ISSN 01460404

Copyright 2019 The Authors. PURPOSE. Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC). METHODS. Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed. RESULTS. There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6–23 years) and that at the time of examination was 40.3 years (range, 22–67 years). The best-corrected visual acuity ranged from -0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases. CONCLUSIONS. Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.

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Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution

Takenouchi T., Sakamoto Y., Sato H., Suzuki H., Uehara T., Ohsone Y., Kosaki K.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 12 ） 2777 - 2780 2018年12月

ISSN 15524825

© 2018 Wiley Periodicals, Inc. The TWIST family is a group of highly conserved basic helix–loop–helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre–Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre–Chotzen syndrome and Sweeney–Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney–Cox syndrome appears to share many characteristics with Barber–Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre–Chotzen syndrome. An amino acid substitution from Glu117 to Asp, both of which are the sole members of negatively charged amino acids, resulted in a prototypic Sweeney–Cox syndrome phenotype. This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney–Cox syndrome phenotype or lethality. The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon.

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Haploinsufficiency of NCOR1 associated with autism spectrum disorder, scoliosis, and abnormal palatogenesis

小崎健次郎

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 11 ） 2466 - 2469 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524825

© 2018 Wiley Periodicals, Inc. NCOR1 (nuclear receptor corepressor 1) is a transcriptional coregulatory protein that regulates the balance between histone acetylation and histone deacetylation. NCOR1 is listed as one of the 3,230 dose-sensitive genes which very rarely show truncating mutations in the pediatric population without severe diseases, even in a heterozygous state. In a large cohort study of intellectual disability/autism spectrum disorder, splicing mutations were identified in two individuals, however, the truncating effects of these splicing mutations have not been examined at the transcription level. We describe a 3-year-old girl who had behavior consistent with autism spectrum disorder, a bifid uvula, and early-onset scoliosis. Trio exome analysis showed a de novo heterozygous mutation at the splice donor site in exon 19 of NCOR1, c.2182 + 1G > T (NM_00190440.1). Reverse transcription polymerase chain reaction assay confirmed that the splicing mutation results in skipping of exon 19, a shift in the reading frame and then to nonsense-mediated mRNA decay. This patient represents the first patient who has had unequivocal documentation of haploinsufficient for the NCOR1 gene. Based on our observations, we conclude that NCOR1 is indeed a human disease-causing gene. We further suggest that bifid uvula, a micro form of cleft palate, may well be causally related to de novo NCOR1 haploinsufficiency, in that a previously reported deletion mapping study of atypical Smith-Magenis syndrome patients with large deletions and cleft palate identified that NCOR1, the only loss-of-function-intolerant gene within the region, is located in the smallest region of overlap.

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SOX17 Mutations in Japanese Patients with Pulmonary Arterial Hypertension.

小崎健次郎

Am J Respir Crit Care Med. 198 （ 9 ） 1231 - 1233 2018年11月

研究論文（学術雑誌）, 共著, 査読有り

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Wilms tumor and congenital malformation syndromes

Uehara T., Kosaki K.

Japanese Journal of Clinical Urology （Japanese Journal of Clinical Urology） 72 （ 11 ） 924 - 926 2018年10月

ISSN 03852393

Sex-dependent phenotypic variability of an SCN5a mutation: Brugada syndrome and sick sinus syndrome

小崎健次郎

Journal of the American Heart Association （Journal of the American Heart Association） 7 （ 18 ） e009387 2018年09月

研究論文（学術雑誌）, 共著, 査読有り

© 2018 The Authors. Background Brugada syndrome (BS) is known to be 9 times more prevalent in males than females. However, little is known about the development of sick sinus syndrome in female members with familial BS. Methods and Results Familial BS patients and family members, both from our institutions and collaborating sites that specialize in clinical care of BS, participated in this study. We collected information on their clinical and genetic background, along with the inheritance patterns of BS. Detailed information on each case with familial BS is described. A total of 7 families, including 25 BS patients (12 females and 13 males), were included. Seven were probands and 18 were family members. Ten out of the 12 female patients and none of the 13 male patients developed sick sinus syndrome. Sudden death or spontaneous ventricular fibrillation occurred in 7 out of 13 male patients and 2 out of 12 female patients. Conclusions Familial BS existed in which female patients developed sick sinus syndrome but male patients did not. Some of those female patients with sick sinus syndrome had unrecognized BS. Information should be collected not only regarding a family history of sudden death or BS, but also whether a pacemaker was implanted in female members.

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A novel homozygous missense mutation in the SH3-binding motif of STAMBP causing microcephaly-capillary malformation syndrome

小崎健次郎

Journal of Human Genetics （Journal of Human Genetics） 63 （ 9 ） 957 - 963 2018年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14345161

© 2018, The Author(s) under exclusive licence to The Japan Society of Human Genetics. Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability. STAMBP interacts with the SH3 domain of STAM and transduces downstream signals from the Jaks-STAM complex. The substitution of Ser236Phe found in the case patient was located in the SH3-binding motif, and we propose the mutation may block STAM binding and subsequently induce STAMBP degradation. Contrary to previously reported STAMBP mutations, the Ser236Phe mutation did not lead to constitutive activation of the PI3K-AKT-mTOR pathway in patient-derived LCLs, as indicated by the expression of phosphorylated S6 ribosomal protein, suggesting that it is not the major pathomechanism underlying the disorder in this patient.

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Further evidence of a causal association between AGO1, a critical regulator of microRNA formation, and intellectual disability/autism spectrum disorder

小崎健次郎

European Journal of Medical Genetics （European Journal of Medical Genetics） S1769-7212 （ 18 ） 30088 - 30090 2018年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17697212

© 2018 Elsevier Masson SAS Among the many regulators of microRNA formation, Argonaute 1 (AGO1) plays critical roles in RNA interference, which controls a wide range of biological activities. Recent large-scale genomic studies have identified at least five patients with intellectual disability/autism spectrum disorder who had de novo mutations in AGO1, but detailed clinical information was not available. The recognizable clinical features that are associated with AGO1 mutations remain to be determined. The proposita was a 15-year-old girl with diffuse hypotonia, infrequent seizures, and intellectual disability with an intelligence quotient of 41. She had characteristic facial features consisting of telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures. Serial computed tomography scans showed progressive calcification in the globus pallidus that became evident during childhood. A whole exome analysis in trio revealed a de novo heterozygous mutation in AGO1, i.e., c.595G > A p.(Gly199Ser). The distinctive facial features, i.e., telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures, closely resembled previously reported patients who had a chromosomal microdeletion encompassing AGO1 locus. The combinatory phenotype of such characteristic facial features and radiographic features, i.e. progressive calcification in the globus pallidus, in the presently reported patient suggest that AGO1 mutations lead to a syndromic form of intellectual disability/autism spectrum disorder. Distinctive facial features with early and progressive calcification in the globus pallidus may be suggestive of the presence of AGO1 mutations.

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Expanding Phenotype of Nephronophthisis-Related Ciliopathy: an Elderly Patient with Homozygous RPGRIP1L Mutation

小崎健次郎

Nephron. 140 （ 1 ） 74 - 78 2018年07月

研究論文（学術雑誌）, 共著, 査読有り

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Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval

小崎健次郎

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 7 ） 1657 - 1661 2018年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524825

© 2018 Wiley Periodicals, Inc. Timothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension. Exome analysis showed a previously undescribed de novo heterozygous mutation in the CACNA1C gene, p.Arg1024Gly. To our knowledge, this patient is the first to exhibit syndactyly and to carry a CACNA1C mutation but to not have QT prolongation, which has long been considered an obligatory feature of Timothy syndrome.

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Systemic lupus erythematosus in a patient with Noonan syndrome-like disorder with loose anagen hair 1: More than a chance association

小崎健次郎

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 7 ） 1662 - 1666 2018年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524825

© 2018 Wiley Periodicals, Inc. Systemic lupus erythematosus (SLE) has been reported among patients with RASopathy. Five patients have been reported: three with SHOC2 variants, one with a PTPN11 variant, and one with a KRAS variant. SHOC2 variant might represent a relatively common predisposing factor for SLE among the RASopathy genes. However, the clinical details were only reported for two patients, while information on the remaining patient appeared only in a tabular format with minimal clinical description. Here, we report a patient with a SHOC2 variant and SLE. The proband was a 28-year-old male patient with intellectual disabilities, a short stature, dysmorphic facial features, and thin hair. He developed hypertrophic cardiomyopathy and afebrile generalized seizures at the ages of 7 and 18 years, respectively. At the age of 24 years, he presented with a 3-day history of intermittent fever accompanied by right chest pain and a malar butterfly rash. He fulfilled both the American College of Rheumatology (ACR) criteria and the Systemic Lupus International Collaborating Clinics (SLICC) criteria for SLE and was successfully treated with prednisolone. Medical exome sequencing identified a de novo SHOC2 variant (c.4A > G, p.S2G). The present report of a second patient who fulfills both the ACR criteria and the SLICC criteria of SLE. We suggest that the association between SHOC2 variant and SLE represents more than a chance association. In the event of fever of unknown origin in patients with constitutional SHOC2 pathogenic variant, SLE should be suspected.

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Development of monomorphic ventricular tachycardia in a patient with fever-induced Brugada syndrome

小崎健次郎

Journal of Arrhythmia （Journal of Arrhythmia） 34 （ 4 ） 465 - 468 2018年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 18804276

© 2018 The Authors. A 50-year-old woman visited the emergency department with a high fever due to pneumonia. Incessant monomorphic ventricular tachycardia occurred and was terminated by intravenous lidocaine. Her ECG during sinus rhythm demonstrated ST segment elevation suggestive of Brugada syndrome (BS). An intensive examination could not detect any structural disease, and typical coved-type ST elevation was unmasked by a pilsicainide injection leading to a diagnosis of BS. An ICD was implanted for secondary prevention of ventricular arrhythmia. The patient has been free from any recurrences of arrhythmia for 3 years.

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Three patients with DeSanto-Shinawi syndrome: Further phenotypic delineation

小崎健次郎

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 6 ） 1335 - 1340 2018年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524825

© 2018 Wiley Periodicals, Inc. Somatic truncating variants of the WAC gene have been observed in patients with hematologic malignancies. Furthermore, de novo heterozygous constitutional pathogenic variants of WAC have recently been shown to cause a syndromic form of intellectual disability, DeSanto-Shinawi syndrome. It is unknown whether the constitutional pathogenic variants observed in the intellectual disability syndrome overlap with the somatic pathogenic variants observed in hematologic abnormalities. Herein, we report three patients with constitutional truncating variants of WAC in an attempt to address the above questions. All three of the patients had mild to moderate intellectual disability and dysmorphic features. We then reviewed the phenotypic features of 19 patients with DeSanto-Shinawi syndrome, including the three currently reported ones: eight and seven patients showed a bulbous nasal tip and short fingers, respectively. As for the pathogenetic mechanism, we demonstrated that the expression level of the mRNA derived from the wildtype allele was higher than that derived from the mutated allele, demonstrating nonsense-mediated mRNA decay. This observation makes a haploinsufficiency mechanism likely. Reviews of the constitutional and somatic pathogenic variants observed in patients with hematologic malignancies showed a significant overlap of the two. To date, no patients with DeSanto-Shinawi syndrome have been reported to have developed hematologic abnormalities, except for one of the three patients reported herein who developed leukopenia and thrombocytopenia at the age of 19 years. Larger data sets are required to determine hematologic prognosis of patients with constitutional WAC variants.

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A paradoxical thrombogenic mutation in factor II at the target site of arthropod bleeding toxin

小崎健次郎

European Journal of Medical Genetics （European Journal of Medical Genetics） S1769-7212 （ 18 ） 30072 - 30077 2018年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17697212

© 2018 Loss-of-function mutations in coagulation cascade proteins lead to bleeding diasthesis. In contrast, gain-of-function mutations in these proteins, which are exceptionally rare, lead to hereditary thrombosis. This is best exemplified by Factor V (i.e., Factor V Leiden) and Factor II (i.e., p.Arg596Leu). Here, we report a family with hereditary thrombosis. The proposita presented with cerebral venous thrombosis accompanied by infarction at the age of 12 years. Despite anticoagulation therapy with oral warfarin, she later developed deep venous thrombosis in her hepatic portal veins at the age of 27 years. A medical exome analysis identified a de novo heterozygous mutation p.Tyr434His in Factor II, which was segregated within the family. A retrospective molecular diagnosis was made using a preserved surgical specimen from the proposita's mother, who had died 10 years earlier. The p.Tyr434 residue, which was substituted in the presently reported family, was located in “exosite I” of thrombin, a critical recognition site for fibrinogen, protein C, and thrombin aptamer. Therefore, the mutant thrombin likely exerted its thrombophilic effect by altering the affinity of thrombin to downstream substrates. Furthermore, the “exosite I” domain of thrombin was inhibited by the arthropod bleeding toxin Triabin (a protein discovered from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis). Our observation that patients with a p.Tyr434His mutation exhibited recurrent thrombosis provides the first proof-of-concept in humans that a pharmacologic agent targeting “exosite I” could be an effective means of specifically modulating the thrombogenic-side of the coagulation system via the inhibition of factor II.

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Successful Total Pericardiectomy for Constrictive Pericarditis in the First Series of Japanese Patients With Mulibrey Nanism

小崎健次郎

Canadian Journal of Cardiology （Canadian Journal of Cardiology） 34 （ 5 ） 690e5 - 690e 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0828282X

© 2018 Canadian Cardiovascular Society Patients with Mulibrey nanism (MUL) present with growth failure and multiple organ manifestations, and MUL is caused by mutations in TRIM37. In this article, we report on the first case series of Japanese patients with MUL who developed congestive heart failure due to constrictive pericarditis. Our case series suggests that early diagnosis and total pericardiectomy before adherence of the pericardium might provide clinical benefit and better prognosis for MUL.

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Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants: Three patients without cardiac defects

小崎健次郎

European Journal of Medical Genetics （European Journal of Medical Genetics） 61 （ 5 ） 243 - 247 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17697212

© 2017 Recently, 7 patients with de novo constitutional non-synonymous mutations in the CDK13 gene were ascertained through a trio exome analysis of a large cohort of 610 patients with congenital cardiac diseases. Despite another report describing 9 additional patients, the clinical spectrum of this condition has yet to be defined. Herein, we report 3 patients with heterozygous constitutional CDK13 mutations, who were ascertained through exome analysis of children with intellectual disability and minor anomalies, who lacked cardiac anomalies. Two patients had a c.2149G > A, p.Gly717Arg mutation, and one had a c.2525A > G, p. Asn842Ser mutation. A review of the previously described patients and those described herein has enabled the following points to be clarified. First, congenital heart diseases are not an essential feature (13/19). Second, nasal features may help syndromic recognition (14/16). Third, widely spaced and peg-shaped teeth may represent a previously unappreciated diagnostic clue for this newly identified syndrome. Here, we show that p.Gly717Arg represents a hotspot in addition to p.Asn842Ser. We suggest that this CDK13-related disorder may represent a clinically recognizable syndrome.

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IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis

Shigemizu D., Miya F., Akiyama S., Okuda S., Boroevich K., Fujimoto A., Nakagawa H., Ozaki K., Niida S., Kanemura Y., Okamoto N., Saitoh S., Kato M., Yamasaki M., Matsunaga T., Mutai H., Kosaki K., Tsunoda T.

Scientific Reports （Scientific Reports） 8 （ 1 ） 5608 2018年04月

© 2018 The Author(s). Insertions and deletions (indels) have been implicated in dozens of human diseases through the radical alteration of gene function by short frameshift indels as well as long indels. However, the accurate detection of these indels from next-generation sequencing data is still challenging. This is particularly true for intermediate-size indels (≥50 bp), due to the short DNA sequencing reads. Here, we developed a new method that predicts intermediate-size indels using BWA soft-clipped fragments (unmatched fragments in partially mapped reads) and unmapped reads. We report the performance comparison of our method, GATK, PINDEL and ScanIndel, using whole exome sequencing data from the same samples. False positive and false negative counts were determined through Sanger sequencing of all predicted indels across these four methods. The harmonic mean of the recall and precision, F-measure, was used to measure the performance of each method. Our method achieved the highest F-measure of 0.84 in one sample, compared to 0.56 for GATK, 0.52 for PINDEL and 0.46 for ScanIndel. Similar results were obtained in additional samples, demonstrating that our method was superior to the other methods for detecting intermediate-size indels. We believe that this methodology will contribute to the discovery of intermediate-size indels associated with human disease.

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Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese

小崎健次郎

Nature Communications （Nature Communications） 9 （ 1 ） 1631 2018年04月

研究論文（学術雑誌）, 共著

© 2018 The Author(s). Understanding natural selection is crucial to unveiling evolution of modern humans. Here, we report natural selection signatures in the Japanese population using 2234 high-depth whole-genome sequence (WGS) data (25.9×). Using rare singletons, we identify signals of very recent selection for the past 2000-3000 years in multiple loci (ADH cluster, MHC region, BRAP-ALDH2, SERHL2). In large-scale genome-wide association study (GWAS) dataset (n = 171,176), variants with selection signatures show enrichment in heterogeneity of derived allele frequency spectra among the geographic regions of Japan, highlighted by two major regional clusters (Hondo and Ryukyu). While the selection signatures do not show enrichment in archaic hominin-derived genome sequences, they overlap with the SNPs associated with the modern human traits. The strongest overlaps are observed for the alcohol or nutrition metabolism-related traits. Our study illustrates the value of high-depth WGS to understand evolution and their relationship with disease risk.

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Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2

小崎健次郎

Brain and Development （Brain and Development） 40 （ 4 ） 343 - 347 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03877604

© 2017 The Japanese Society of Child Neurology Introduction: The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2. Patients: The proband was the father, aged 30, and the son was aged 3. Both of them were born uneventfully to nonconsanguineous parents. While the father first walked at the age of 19 months, the son was unable to walk at age 3 years. In both, knee and ankle reflexes were absent and sensation was intact. Serum creatine kinase levels were normal. The son showed congenital arthrogryposis and underwent orthopedic corrections for talipes calcaneovalgus. Investigation of the father at the age of 5 years revealed normal results on nerve conduction studies and sural nerve biopsy. Electromyography showed chronic neurogenic change, and muscle biopsy showed features suggestive of denervation. The father was diagnosed clinically with a sporadic distal SMA. Follow-up studies showed very slow progression. Investigations and results: Next-generation and Sanger sequencing revealed a deleterious mutation in BICD2: c.1667A>G, p.Tyr556Cys, in this family. Discussion: BICD2 is a cytoplasmic conserved motor-adaptor protein involved in anterograde and retrograde transport along the microtubules. Next-generation sequencing will further clarify the genetic basis of non-5q SMA.

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Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells

小崎健次郎

Scientific Reports （Scientific Reports） 8 （ 1 ） 6069 2018年04月

研究論文（学術雑誌）, 共著, 査読有り

© 2018 The Author(s). Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas. With the use of a cell-based drug screening assay, we have now identified the antiallergy drug tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) as an inhibitor of EMT and found that it attenuated the expression of mesenchymal markers and angiogenesis-related genes in NF1-mutated sNF96.2 cells and in neurofibroma cells from NF1 patients. Tranilast also suppressed the proliferation of neurofibromin-deficient cells in vitro more effectively than it did that of intact cells. In addition, tranilast inhibited sNF96.2 cell migration and proliferation in vivo. Knockdown of type III collagen (COL3A1) also suppressed the proliferation of neurofibroma cells, whereas expression of COL3A1 and SOX2 was increased in tranilast-resistant cells, suggesting that COL3A1 and the transcription factor SOX2 might contribute to the development of tranilast resistance.

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Large number of cutaneous neurofibromas beyond age-appropriate incidence in a patient with a large deletion of NF1.

小崎健次郎

J Dermatol. 45 （ 3 ） 363 - 364 2018年03月

研究論文（学術雑誌）, 共著, 査読有り

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Growth pattern of Rahman syndrome

小崎健次郎

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 3 ） 712 - 714 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524825

© 2018 Wiley Periodicals, Inc. Recently, in a cohort study with “overgrowth syndrome with intellectual disability,” five subjects were reported to have de novo heterozygous truncating variants in HIST1H1E, which encodes linker histone H 1.4. However, their growth pattern appeared complex that four out of five patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Herein, we report a female patient with intellectual disability and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup p.(Ala145Glyfs*51). The physical features of the proposita were essentially the same as those observed in patients with the aforementioned HIST1H1E-related overgrowth syndrome. Our review of the growth trajectories in seven patients showed that five of seven patients did not exhibit skeletal overgrowth. This “lack of overgrowth in overgrowth syndrome” is reminiscent of a subset of patients with a short stature who have Sotos syndrome, a prototypic overgrowth syndrome. Considering this complexity in growth, this newly identified condition should be referred to as Rahman syndrome.

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Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

小崎健次郎

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 2 ） 431 - 437 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524825

© 2017 Wiley Periodicals, Inc. Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

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Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms

小崎健次郎

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 2 ） 404 - 408 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15524825

© 2017 Wiley Periodicals, Inc. Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we report female siblings with biallelic mutations in LARS2, p.Glu294Lys, and p.Thr519Met, who were classified as type 2. The proposita developed progressive sensorineural hearing loss at 18 months and pervasive developmental disorder at 8 years, with repetitive behavior, insistence on sameness, attention deficit, tic, irritability, and an ataxic gait. At age 15 years, she was diagnosed as having primary amenorrhea with elevated FSH and LH and a decreased estradiol; ultrasound and magnetic resonance imaging examinations revealed a small uterus and no detectable ovaries. The proposita's younger sister presented with neonatal sensorineural hearing loss and a mild delay in motor and speech development. She was diagnosed as having primary amenorrhea with endocrinologic and radiographic findings that were comparable to those of her sister. She had difficulty with reading comprehension, and had trouble with open-ended test questions at 12 years of age. We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise.

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Targeted reversion of induced pluripotent stem cells from patients with human cleidocranial dysplasia improves bone regeneration in a rat calvarial bone defect model

小崎健次郎

Stem Cell Research and Therapy （Stem Cell Research and Therapy） 9 （ 1 ） 12 2018年01月

研究論文（学術雑誌）, 共著, 査読有り

© 2018 The Author(s). Background: Runt-related transcription factor 2 (RUNX2) haploinsufficiency causes cleidocranial dysplasia (CCD) which is characterized by supernumerary teeth, short stature, clavicular dysplasia, and osteoporosis. At present, as a therapeutic strategy for osteoporosis, mesenchymal stem cell (MSC) transplantation therapy is performed in addition to drug therapy. However, MSC-based therapy for osteoporosis in CCD patients is difficult due to a reduction in the ability of MSCs to differentiate into osteoblasts resulting from impaired RUNX2 function. Here, we investigated whether induced pluripotent stem cells (iPSCs) properly differentiate into osteoblasts after repairing the RUNX2 mutation in iPSCs derived from CCD patients to establish normal iPSCs, and whether engraftment of osteoblasts derived from properly reverted iPSCs results in better regeneration in immunodeficient rat calvarial bone defect models. Methods: Two cases of CCD patient-derived induced pluripotent stem cells (CCD-iPSCs) were generated using retroviral vectors (OCT3/4, SOX2, KLF4, and c-MYC) or a Sendai virus SeVdp vector (KOSM302L). Reverted iPSCs were established using programmable nucleases, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-derived RNA-guided endonucleases, to correct mutations in CCD-iPSCs. The mRNA expressions of osteoblast-specific markers were analyzed using quantitative reverse-transcriptase polymerase chain reaction. iPSCs-derived osteoblasts were transplanted into rat calvarial bone defects, and bone regeneration was evaluated using microcomputed tomography analysis and histological analysis. Results: Mutation analysis showed that both contained nonsense mutations: one at the very beginning of exon 1 and the other at the initial position of the nuclear matrix-targeting signal. The osteoblasts derived from CCD-iPSCs (CCD-OBs) expressed low levels of several osteoblast differentiation markers, and transplantation of these osteoblasts into calvarial bone defects created in rats with severe combined immunodeficiency showed poor regeneration. However, reverted iPSCs improved the abnormal osteoblast differentiation which resulted in much better engraftment into the rat calvarial bone defect. Conclusions: Taken together, these results demonstrate that patient-specific iPSC technology can not only provide a useful disease model to elucidate the role of RUNX2 in osteoblastic differentiation but also raises the tantalizing prospect that reverted iPSCs might provide a practical medical treatment for CCD.

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Natural course and characteristics of cutaneous neurofibromas in neurofibromatosis 1

小崎健次郎

Journal of Dermatology （Journal of Dermatology） 45 （ 1 ） 53 - 57 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03852407

© 2017 Japanese Dermatological Association Neurofibromatosis 1 (NF1) is characterized by cutaneous, neurological and osseous manifestations. Most NF1 patients develop cutaneous neurofibromas. However, time-dependent change with aging and the predilection site of cutaneous neurofibromas remain unclear. To clarify the natural course and characteristics of cutaneous neurofibromas, a retrospective study was conducted for 57 NF1 patients who were treated at the Department of Dermatology of Tottori University Hospital between January 2007 and April 2016. For each patient, we investigated the time-dependent changes and the numbers of cutaneous neurofibromas in four body surface regions. There was a positive correlation between age and number of cutaneous neurofibromas (r = 0.75, P < 0.001). Cutaneous neurofibromas were located on the trunk (60.2%), lower limbs (16.1%), upper limbs (14.4%), and head and neck (9.2%). There was no significant relationship between each body type (e.g. obese or thin) and cutaneous neurofibromas. With respect to the year-to-year percentage change in cutaneous neurofibromas, the average annual rate of increase was 0.21 (range, −0.71 to 1.2). The number of cutaneous neurofibromas had increased in approximately 61% of the patients 1 year later. Our data will enable physicians to estimate the overall state of cutaneous neurofibromas in NF1 and will be useful for handling cutaneous manifestations before they become a serious condition.

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CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations.

小崎健次郎

Elife. 2017年11月

研究論文（学術雑誌）, 共著, 査読有り

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Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework.

小崎健次郎

Adv Exp Med Biol. 1031 55 - 94 2017年

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Case of dominant dystrophic epidermolysis bullosa with amniotic band syndrome.

小崎健次郎

J Dermatol. 44 （ (1) ） 102 - 103 2017年

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Role of a heterotrimeric G-protein, Gi2, in the corticogenesis: possible involvement in periventricular nodular heterotopia and intellectual disability.

小崎健次郎

J Neurochem 140 （ (1) ） 82 - 95 2017年

研究論文（学術雑誌）, 共著

An RyR2 mutation found in a family with a short-coupled variant of torsade de pointes.

小崎健次郎

Int J Cardiol. 227 367 - 369 2017年

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Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation.

小崎健次郎

Am J Med Genet A. 173 （ (1) ） 250 - 253 2017年

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Changeability of the fully methylated status of the 15q11.2 region in induced pluripotent stem cells derived from a patient with Prader-Willi syndrome.

小崎健次郎

Congenit Anom (Kyoto). 57 （ (4) ） 96 - 103 2017年

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A Novel SCN5A Mutation Found in a Familial Case of Long QT Syndrome Complicated by Severe Left Ventricular Dysfunction

小崎健次郎

Can J Cardiol. 33 （ (4) ） 554 2017年

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A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly.

小崎健次郎

BMC Med Genet. 18 （ (1) ） 4 2017年

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Diagnostic Use of Computational Retrotransposon Detection: Successful Definition of Pathogenetic Mechanism in Ciliopathy Phenotype

小崎健次郎

Am J Med Genet A 173 （ (5) ） 1353 - 1357 2017年

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Mitochondrial mutations in maternally inherited hearing loss.

小崎健次郎

BMC Med Genet. 18 （ (1) ） 32 2017年

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Novel MCA/ID syndrome with ASH1L mutation.

小崎健次郎

Am J Med Genet A. 173 （ (6) ） 1644 - 1648 2017年

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Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene.

小崎健次郎

Am J Med Genet A. 173 （ (6) ） 1631 - 1634 2017年

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Initiating an undiagnosed diseases program in the Western Australian public health system.

小崎健次郎

Orphanet J Rare Dis. 12 （ (1) ） 83 2017年

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A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate.

小崎健次郎

J Hum Genet 2017年

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YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

小崎健次郎

Am J Hum Genet. 100 （ (6) ） 907 - 925 2017年

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Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement.

小崎健次郎

Sci Rep. 7 （ (1) ） 3552 2017年

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Siblings with optic neuropathy and RTN4IP1 mutation.

小崎健次郎

J Hum Genet 2017年

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Expansion of the phenotype of Kosaki overgrowth syndrome.

小崎健次郎

Am J Med Genet A 173 （ 9 ） 2422 - 2427 2017年

研究論文（学術雑誌）, 共著, 査読有り

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Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia.

小崎健次郎

Horm Res Paediatr. 88 （ 5 ） 316 - 323 2017年

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Co-occurrence of Sturge-Weber syndrome and Klippel-Trenaunay-Weber syndrome phenotype:Consideration of the historical aspect.

小崎健次郎

Am J Med Genet A. 173 （ 10 ） 2831 - 2833 2017年

研究論文（学術雑誌）, 共著, 査読有り

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Preaxial polydactyly in an individual with Wiedemann-Steiner Syndrome caused by a novel nonsense mutation in KMT2A.

小崎健次郎

Am J Med Genet. 173 （ 10 ） 2821 - 2825 2017年

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Truncating mutation in CSNK2B and myoclonic epilepsy.

小崎健次郎

Human Mutation 38 （ 11 ） 1611 - 1612 2017年

研究論文（学術雑誌）, 共著, 査読有り

A novel genetic syndrome with STARD9 mutation and abnormal spindle morphology.

小崎健次郎

Am J Med Genet A. 173 （ 10 ） 2690 - 2696 2017年

研究論文（学術雑誌）, 共著, 査読有り

A novel BBS10 mutation identified in a patient with Bardet-Biedl syndrome with a violent emotional outbreak

小崎健次郎

Hum Genome Var. 4 17033 2017年

査読有り

Clinical severity in Japanese patients with neurofibromatosis 1 based on DNB classification.

小崎健次郎

J Dermatol. 44 （ 11 ） 1262 - 1267 2017年

A genome-wide association analysis identifies PDE1A|DNAJC10 locus on chromosome 2 associated with idiopathic pulmonary arterial hypertension in a Japanese population.

小崎健次郎

Oncotarget. 8 （ 43 ） 74917 - 74926 2017年

研究論文（学術雑誌）

Gorlin syndrome-derived induced pluripotent stem cells are hypersensitive to hedgehog-mediated osteogenic induction.

小崎健次郎

PLoS One. 12 （ 10 ） e0186879 2017年

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A case of mature teratoma with a falsely high serum estradiol value measured with an immunoassay.

小崎健次郎

J Pediatr Endocrinol Metab. 29 （ (6) ） 737 - 739 2016年

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Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome.

小崎健次郎

Am J Med Genet. 170 （ (7) ） 1863 - 1867 2016年

研究論文（学術雑誌）

Characterization of the STK11 splicing variant as a normal splicing isomer in a patient with Peutz-Jeghers syndrome harboring genomic deletion of the STK11 gene.

小崎健次郎

Hum Genome Var. 2016年

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Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts.

小崎健次郎

Sci Rep. 2016年

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Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock-Carey syndrome phenotype.

小崎健次郎

Am J Med Genet. 170 （ (10) ） 2587 - 2590 2016年

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Homozygosity for moyamoya disease risk allele leads to moyamoya disease with extracranial systemic and pulmonary vasculopathy.

小崎健次郎

Am J Med Genet. 170 （ (9) ） 2453 - 2456 2016年

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Hirschsprung disease as a yet undescribed phenotype in a patient with ARID1B mutation.

小崎健次郎

Am J Med Genet 170 （ (12) ） 3249 - 3252 2016年

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Jacobsen syndrome, Braddock-Carey syndrome, and beyond: Reflections on intellectual disability accompanied with thrombocytopenia

小崎健次郎

Am J Med Genet. 170 （ (10) ） 2578 - 2579 2016年

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Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy.

小崎健次郎

Eur J Hum Genet. 24 （ (12) ） 1702 - 1706 2016年

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Systemic and maxillofacial characteristics of eleven Japanese children with Russell-Silver syndrome.

小崎健次郎

Congenit Anom. 56 （ (5) ） 217 - 225 2016年

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Further evidence of a mutation in CDC42 as a cause of a recognizable syndromic form of thrombocytopenia.

小崎健次郎

Am J Med Genet A 170 （ (4) ） 852 - 855 2016年

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ALDH18A1-related cutis laxa syndrome with cyclic vomiting

小崎健次郎

Brain Dev 38 （ (7) ） 678 - 684 2016年

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Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24-32.

小崎健次郎

Heart Vessels. 31 （ (10) ） 1717 - 1723 2016年

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Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient needs

小崎健次郎

Mol Genet Metab. 116 （ 4 ） 223 - 225 2015年12月

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A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.

小崎健次郎

PLoS Genet 11 （ 11 ） e1005581 2015年11月

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Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay.

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Am J Med Genet. 167 （ 11 ） 2822 - 2825 2015年11月

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TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis.

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Sci Rep 2015年10月

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Late-onset epileptic spasms in a female patient with a CASK mutation.

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Brain Dev 37 （ 9 ） 919 - 923 2015年10月

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Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome in a boy with Loeys-Dietz syndrome.

小崎健次郎

Am J Med Genet A 167 （ 10 ） 2435 - 2439 2015年10月

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Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders

小崎健次郎

Clin Genet 88 （ 3 ） 288 - 292 2015年09月

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Adult Phenotype of Russell-Silver Syndrome: A Molecular Support for Barker-Brenner's Theory.

小崎健次郎

Congenital Anom 55 （ 3 ） 167 - 169 2015年08月

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Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications.

小崎健次郎

Brain Dev 37 （ 5 ） 515 - 526 2015年05月

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Primary Microcephaly With Anterior Predominant Pachygyria Caused by Novel Compound Heterozygous Mutations in ASPM.

小崎健次郎

Pediatr Neurol 52 （ 5 ） e7 - e8 2015年05月

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Mosaic overgrowth with fibroadipose hyperplasia due to AKT1 mutation

小崎健次郎

Am J Med Genet A 167 （ 4 ） 907 - 909 2015年04月

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Sudden death in a case of megalencephaly capillary malformation associated with a de novo mutation in AKT3

小崎健次郎

Childs Nerv Syst 31 （ 3 ） 465 - 471 2015年03月

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A combination of targeted enrichment methodologies for whole-exome sequencing reveals novel pathogenic mutations.

小崎健次郎

Sci Rep 19 （ 5 ） 9331 2015年03月

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Truncating mutation in NFIA causes brain malformation and urinary tract defects

小崎健次郎

Human Genome Variation 2 15007 2015年02月

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Novel overgrowth syndrome phenotype due to recurrent de novo PDGFRB mutation

小崎健次郎

J Pediatr 166 （ (2) ） 483 - 486 2015年02月

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Paramagnetic Signals in the Globus Pallidus as Late Radiographic Sign of Juvenile-Onset GM1 Gangliosidosis.

小崎健次郎

Pediatr Neurol. 166 （ (2) ） 483 - 486 2015年02月

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Porencephaly in a fetus and HANAC in her father: Variable expression of COL4A1 mutation.

小崎健次郎

Am J Med Genet 167 （ (1) ） 156 - 158 2015年01月

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Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: Clinical evidence of crosslink between FGFR and RAS signaling pathways.

小崎健次郎

Am J Med Genet A 164 （ (11) ） 2869 - 2872 2014年

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A novel mutation in SOX3 polyalanine tract: a case of kabuki syndrome with combined pituitary hormone deficiency harboring double mutations in MLL2 and SOX3.

小崎健次郎

Pituitary 17 （ (6) ） 569 - 574 2014年

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Somatic CTNNB1 mutation in hepatoblastoma from a patient withSimpson-Golabi-Behmel syndrome and germline GPC3 mutation.

小崎健次郎

Am J Med Genet A 164A （ (4) ） 392 - 396 2014年

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Multiple café au lait spots in familial patients with MAP2K2 mutation

小崎健次郎

Am J Med Genet A 164 （ (2) ） 392 - 396 2014年

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Family History and BRCA1/BRCA2 Status Among Japanese Ovarian Cancer Patients and Occult Cancer in a BRCA1 Mutant Case

小崎健次郎

Jpn J Clin Oncol 44 （ (1) ） 49 - 56 2014年

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1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay.

小崎健次郎

Am J Med Genet A. 164 （ (2) ） 456 - 460 2014年

研究論文（学術雑誌）, 共著

SOX9 dimerization domain mutation mimicking type 2 collagen disorder phenotype

小崎健次郎

Eur J Med Genet 57 （ (6) ） 298 - 301 2014年

研究論文（学術雑誌）, 共著

Progressive cognitive decline in an adult patient with cleidocranial dysplasia.

小崎健次郎

Eur J Med Genet. 57 （ (7) ） 319 - 321 2014年

研究論文（学術雑誌）, 共著

Endocrinological Characteristics of 25 Japanese Patients with CHARGE Syndrome

小崎健次郎

Clin Pediatr Endocrinol. 23 （ (2) ） 45 - 51 2014年

研究論文（学術雑誌）, 共著

The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations

小崎健次郎

Am J Med Genet A. 164 （ (8) ） 1899 - 1908 2014年

研究論文（学術雑誌）, 共著

Coexistence of two distinct fascinating cardiovascular disorders: Heterotaxy syndrome with left ventricular non-compaction and vasospastic angina.

小崎健次郎

Int J Cardiol 174 （ (2) ） e54 - 56 2014年

研究論文（学術雑誌）, 共著

Clinical Utility of an Array Comparative Genomic Hybridization Analysis for Williams Syndrome

小崎健次郎

Congenit Anom (Kyoto) 54 （ (4) ） 225 - 227 2014年

研究論文（学術雑誌）

Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes

小崎健次郎

Stem Cell Reports 2 （ (5) ） 648 - 661 2014年

研究論文（学術雑誌）

Four-decade-old mummified umbilical tissue making retrospective molecular diagnosis of ornithine carbamoyltransferase deficiency

小崎健次郎

Am J Med Genet A 164 （ (10) ） 2679 - 2681 2014年

研究論文（学術雑誌）, 共著

The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: A validation study.

小崎健次郎

Genet Test Mol Biomarkers 18 （ (11) ） 722 - 735 2014年

研究論文（学術雑誌）, 共著

KIF1A mutation in a patient with progressive neurodegeneration.

小崎健次郎

J Hum Genet 59 （ (11) ） 639 - 641 2014年

研究論文（学術雑誌）, 共著

Catastrophic Autonomic Crisis With Cardiovascular Collapse in Spinal Muscular Atrophy With Respiratory Distress Type 1.

小崎健次郎

J Child Neurol 28 （ (7) ） 949 - 951 2013年08月

研究論文（学術雑誌）, 共著, 査読有り

Severe obstructive sleep apnea in Loeys-Dietz syndrome successfully treated using continuous positive airway pressure

小崎健次郎

Am J Med Genet A 161A （ 7 ） 1733 - 1736 2013年07月

研究論文（学術雑誌）, 共著

遺伝性疾患におけるターゲットリシーケンシングの有用性 (第1土曜特集エクソーム解析 : 成果と将来)　

小崎健次郎

医学のあゆみ 245 （ (5) ） 369 - 371 2013年

研究論文（学術雑誌）, 単著

Concurrent deletion of BMP4 and OTX2 genes, two master genes in ophthalmogenesis.

小崎健次郎

Eur J Med Genet 56 （ 1 ） 50-53 2013年

研究論文（学術雑誌）, 共著, 査読有り

Experience of Risk-reducing Salpingo-oophorectomy for a BRCA1 Mutation Carrier and Establishment of a System Performing a Preventive Surgery for Hereditary Breast and Ovarian Cancer Syndrome in Japan: Our Challenges for the Future.

小崎健次郎

Jpn J Clin Oncol 43 （ 5 ） 515-519 2013年

研究論文（学術雑誌）, 共著, 査読有り

Large Congenital Melanocytic Nevi With Atypical Teratoid/Rhabdoid Tumor.

小崎健次郎

Pediatr Blood Cancer 60 （ (7) ） 1240 - 1241 2013年

研究論文（学術雑誌）, 共著, 査読有り

Persistent hypertension despite successful dilation of a stenotic renal artery in a boy with neurofibromatosis type 1.

小崎健次郎

Am J Med Genet A 161 （ 5 ） 1154-1157 2013年

研究論文（学術雑誌）, 共著, 査読有り

Potential Teratogenicity of Methimazole: Exposure of Zebrafish Embryos to Methimazole Causes Similar Developmental Anomalies to Human Methimazole Embryopathy.

小崎健次郎

Birth Defects Res B Dev Reprod Toxicol 98 （ (3) ） 222 - 229 2013年

研究論文（学術雑誌）, 共著, 査読有り

Daytime somnolence in an adult with Smith-Magenis syndrome

小崎健次郎

American Journal of Medical Genetics 161A （ (7) ） 1803 - 1805 2013年

研究論文（学術雑誌）, 共著

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients.

小崎健次郎

J Hum Gene 58 （ (12) ） 794 - 798 2013年

研究論文（学術雑誌）, 共著

Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype.

小崎健次郎

Am J Med Genet A 161 （ (12) ） 3057 - 3062 2013年

研究論文（学術雑誌）, 共著

Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study.

小崎健次郎

Orphanet J Rare Dis. 8 （ (1) ） 172 2013年

研究論文（学術雑誌）, 共著

Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis

小崎健次郎

Am J Hum Genet. 93 （ (5) ） 945 - 956 2013年

研究論文（学術雑誌）, 共著

Hydrocephalus with Hirschsprung disease: severe end of X-linked hydrocephalus spectrum.

小崎健次郎

Am J Med Genet A 158 （ A(4) ） 812-5 2012年

研究論文（学術雑誌）, 共著, 査読有り

EEC syndrome-like phenotype in a patient with an IRF6 mutation.

小崎健次郎

Am J Med Genet A 158 （ A(5) ） 1219-20 2012年

研究論文（学術雑誌）, 共著, 査読有り

Ophthalmic features of CHARGE syndrome with CHD7 mutations.

小崎健次郎

Am J Med Genet A 158 （ 3 ） 514-518 2012年

研究論文（学術雑誌）, 共著, 査読有り

Congenital corneal staphyloma as a complication of Kabuki syndrome.

小崎健次郎

Am J Med Genet A 158 （ 8 ） 2000-2002 2012年

研究論文（学術雑誌）, 共著, 査読有り

Age-dependent change in behavioral feature in Rubinstein-Taybi syndrome.

小崎健次郎

Congenit Anom 52 （ 2 ） 82-86 2012年

研究論文（学術雑誌）, 共著, 査読有り

12q14 microdeletion syndrome and short stature with or without relative macrocephaly.

小崎健次郎

Am J Med Genet A 158 （ 10 ） 2542-2544 2012年

研究論文（学術雑誌）, 共著, 査読有り

Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting.

小崎健次郎

Am J Med Genet A 158 （ 10 ） 2537-2541 2012年

研究論文（学術雑誌）, 共著, 査読有り

Tissue-limited ring chromosome 18 mosaicism as a cause of Pitt-Hopkins syndrome.

小崎健次郎

Am J Med Genet A 158 （ 10 ） 2621-2623 2012年

研究論文（学術雑誌）, 共著, 査読有り

The germline TP53 mutation c.722 C>T promotes bone and liver tumorigenesis at a young age.

小崎健次郎

Pediatr Blood Cancer 59 （ 7 ） 1332-1333 2012年

研究論文（学術雑誌）, 共著, 査読有り

Maternal uniparental isodisomy and heterodisomy on chromosome 6 encompassing a CUL7 gene mutation causing 3M syndrome.

小崎健次郎

Clin Genet 80 478-483 2011年

研究論文（学術雑誌）, 共著, 査読有り

Reversible diffuse white matter lesion in Alagille syndrome.

小崎健次郎

Pediatric Neurology 45 （ 1 ） 54-6 2011年

研究論文（学術雑誌）, 共著, 査読有り

Branchial arch defects and 19p13.12 microdeletion: Defining the critical region into a 0.8M base interval.

小崎健次郎

American Journal of Medical Genetics 155A （ 9 ） 2212-4 2011年

研究論文（学術雑誌）, 共著, 査読有り

Reproductive success in patients with Hallermann-Streiff syndrome.

小崎健次郎

American Journal of Medical Genetics 155A （ 9 ） 2311-3 2011年

研究論文（学術雑誌）, 共著, 査読有り

Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation.

小崎健次郎

Proc Natl Acad Sci U S A 108 2468-2473 2011年

研究論文（学術雑誌）, 共著, 査読有り

Role of rare cases in deciphering the mechanisms of congenital anomalies: CHARGE syndrome research.

小崎健次郎

Congenit Anom 51 51:12-15. 2011年

研究論文（学術雑誌）, 単著, 査読有り

Overgrowth of prenatal onset associated with submicroscopic 9q22.3 deletion.

小崎健次郎

American Journal of Medical Genetics 155 903-905. 2011年

研究論文（学術雑誌）, 共著, 査読有り

Monozygotic twins of Rubinstein-Taybi Syndrome discordant for glaucoma.

小崎健次郎

American Journal of Medical Genetics 155 1189-1191. 2011年

研究論文（学術雑誌）, 共著, 査読有り

Surgical treatment for scoliosis in patients with Shprintzen-Goldberg Syndrome.

小崎健次郎

Journal of Pediatric Orthopedics 31 186-193 2011年

研究論文（学術雑誌）, 共著, 査読有り

Survival of a male mosaic for PORCN mutation with mild focal dermal hypoplasia phenotype.

小崎健次郎

Pediatric Dermatology 28 （ 5 ） 550-4 2011年

研究論文（学術雑誌）, 共著, 査読有り

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: a case report and a pathological insight into pilosebaceous anomaly.

小崎健次郎

American Journal of Dermatopathology, 33 （ 4 ） 403-6. 2011年

研究論文（学術雑誌）, 共著, 査読有り

Severe Developmental Delay in a Patient with 7p21.1-p14.3 Microdeletion Spanning the TWIST Gene and the HOXA Gene Cluster.

小崎健次郎

Mol Syndromol 2 （ 1 ） 45-49 2011年

研究論文（学術雑誌）, 共著, 査読有り

遺伝子診療学研究の進歩　再生医学との連携（遺伝子診療学（第2版）--遺伝子診断の進歩とゲノム治療の展望）--（遺伝子診断）

小崎健次郎　奥野博庸、小崎健次郎

日本臨床 68 （増刊号） 71 - 75 2010年

研究論文（学術雑誌）, 共著

Characterization of a de novo balanced t(4;20)(q33;q12) translocation in a patient with mental retardation.

小崎健次郎

American Journal of Medical Genetics 152A （ 12 ） 3057-67 2010年

研究論文（学術雑誌）, 共著, 査読有り

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation.

小崎健次郎

Clin Transplant 24 （ (6) ） 855-861 2010年

研究論文（学術雑誌）, 共著, 査読有り

Correlation between genotype and supernumerary tooth formation in cleidocranial dysplasia.

小崎健次郎

Orthod Craniofac Res 45 （ 13 ） 197-202 2010年

研究論文（学術雑誌）, 共著, 査読有り

In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1.

小崎健次郎

Proceedings of the National Academy of Sciences of the United States of America 107 16331-16335 2010年

研究論文（学術雑誌）, 共著, 査読有り

Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A2 and prostacyclin

小崎健次郎

American Journal of Medical Genetics 152 1919-1924 2010年

研究論文（学術雑誌）, 共著, 査読有り

Late manifestations of Tricho-Rhino-Pharangeal syndrome in a patient: Expanded skeletal phenotype in adulthood.

小崎健次郎

American Journal of Medical Genetics, 152 2115-2119 2010年

研究論文（学術雑誌）, 共著, 査読有り

Cri-du-chat syndrome cytogenetically cryptic recombination aneusomy of chromosome 5: Implications in recurrence risk estimation.

小崎健次郎

Molecular Syndromology 1 95-98 2010年

研究論文（学術雑誌）, 共著, 査読有り

Juvenile muscular atrophy of a unilateral upper extremity (Hirayama disease) in a patient with CHARGE syndrome,

小崎健次郎

Molecular Syndromology 1 91-94 2010年

研究論文（学術雑誌）, 共著, 査読有り

Brachmann-de Lange syndrome with congenital diaphragmatic hernia and NIPBL gene mutation.

小崎健次郎

Congenital Anomalies 50 129-132 2010年

研究論文（学術雑誌）, 共著, 査読有り

Two patients with Rubinstein-Taybi syndrome and severe pulmonary interstitial involvement.

小崎健次郎

American Journal of Medical Genetics 152 1844-1846 2010年

研究論文（学術雑誌）, 共著, 査読有り

Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism.

小崎健次郎

European Journal of Pediatrics, 169 839-844 2010年

研究論文（学術雑誌）, 共著, 査読有り

A case of Tessier number 7 cleft with severe micrognathia: prenatal sonographic and three-dimensional helical computed tomographic images.

小崎健次郎

Prenatal Diagnosis 30 159-161 2010年

研究論文（学術雑誌）, 共著, 査読有り

Transverse limb defect in a patient with Jacobsen syndrome: Concurrence of malformation and disruption.

小崎健次郎

American Journal of Medical Genetics, 152A 1033-1035 2010年

研究論文（学術雑誌）, 共著, 査読有り

Ocular complications in Mulvihill-Smith syndrome.

小崎健次郎

Eye (Lond), 24 1123-1124. 2010年

研究論文（学術雑誌）, 共著, 査読有り

Interstitial microdeletion of 4p16.3: Contribution of WHSC1 haploinsufficiency to the pathogenesis of developmental delay in Wolf-Hirschhorn syndrome.

小崎健次郎

American Journal of Medical Genetics 152 1028–1032. 2010年

研究論文（学術雑誌）, 共著, 査読有り

Microdeletion of the Down syndrome critical region at 21q22.

小崎健次郎

American Journal of Medical Genetics 152 （ 13 ） 950–953. 2010年

研究論文（学術雑誌）, 共著, 査読有り

形態異常へのアプローチ

小崎健次郎

小児内科 42 1235 - 1238 2010年

研究論文（学術雑誌）, 単著

臨床遺伝学の知識を深めよう

小崎健次郎

日本医師会雑誌　特集「臨床遺伝学の進歩と日常診療」 537 2010年

研究論文（学術雑誌）, 単著

Shprintzen-Goldberg症候群に伴った側彎症の4例

小崎健次郎　岡田英次朗、松本守雄、渡辺航太、塩野雄太、飯塚慎吾、戸山芳昭、千葉一裕、小崎健次郎

臨床整形外科 44 1063 - 1069 2009年

研究論文（学術雑誌）, 共著

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.

小崎健次郎

European Journal of Human Genetics 17 1325-1335 2009年

研究論文（学術雑誌）, 共著, 査読有り

Diagnosis of Russell-Silver syndrome by the combined bisulfite restriction analysis - Denaturing high-performance liquid chromatography assay.

小崎健次郎

Genetic Testing and Molecular Biomarkers, 13 623-630 2009年

研究論文（学術雑誌）, 共著, 査読有り

Association between patient age at the time of surgical treatment for endometriosis and aryl hydrocarbon receptor repressor polymorphism.

小崎健次郎

Fertility and Sterility, 92 1240-1242. 2009年

研究論文（学術雑誌）, 共著, 査読有り

Effects of the CYP2D6*10 alleles and co-medication with CYP2D6-dependent drugs on risperidone metabolism in patients with schizophrenia.

小崎健次郎

Human Psychopharmacology, 24 301-308. 2009年

研究論文（学術雑誌）, 共著, 査読有り

Caudal regression and tracheoesophageal malformation induced by adriamycin: A novel chick model of VATER association.

小崎健次郎

Pediatric Research, 65 607-612. 2009年

研究論文（学術雑誌）, 共著, 査読有り

Case report: Adult phenotype of Mulvihill-Smith syndrome.

小崎健次郎

American Journal of Medical Genetics 149 496 - 500 2009年

研究論文（学術雑誌）, 共著

Russell-Silver症候群

小崎健次郎

小児内科 41 増刊号 280 - 290 2009年

研究論文（学術雑誌）, 単著

CHARGE症候群

小崎健次郎

小児内科 41 増刊号 330 - 331 2009年

研究論文（学術雑誌）, 単著

過成長症候群

小崎健次郎

小児科臨床 62 2186 - 2187 2009年

研究論文（学術雑誌）, 単著

MLPA法を用いたサブテロメア異常の検出

小崎健次郎　大木寛生、小崎健次郎

小児内科 41 （増刊号） 926 - 928 2009年

研究論文（学術雑誌）, 共著

遺伝子診断の臨床応用の促進

小崎健次郎

医学のあゆみ　特集臨床ゲノム研究 225 835 - 839 2008年

研究論文（学術雑誌）, 単著

サブテロメア異常(微細欠失・微細重複)

小崎健次郎

小児科臨床 61 405 - 406 2008年

研究論文（学術雑誌）, 単著

Two distinctive classic genetic syndromes, 22q11.2 deletion syndrome and Angelman syndrome, occurring within the same family.

小崎健次郎

American Journal of Medical Genetics 149 702-705 2008年

研究論文（学術雑誌）, 共著, 査読有り

Characteristic phenotype of immortalized periodontal cells isolated from a Marfan syndrome type I patient

小崎健次郎

Cell and Tissue Research 331 461-472 2008年

研究論文（学術雑誌）, 共著, 査読有り

Tietz syndrome: Unique phenotype specific to mutations of MITF nuclear localization signal

小崎健次郎

Clinical Genetics 74 93-95 2008年

研究論文（学術雑誌）, 共著, 査読有り

Neocentromere marker chromosome of distal 3q mimicking dup(3q) syndrome phenotype

小崎健次郎

American Journal of Medical Genetics 146 1967-1971 2008年

研究論文（学術雑誌）, 共著

Endocrine and radiological studies in patients with molecularly confirmed CHARGE syndrome

小崎健次郎

Journal of Clinical Endocrinology and Metabolism 93 920-924 2008年

研究論文（学術雑誌）, 共著, 査読有り

Influence of Methylenetetrahydrofolate Reductase and Reduced Folate Carrier 1 Polymorphisms on Toxicities during Maintenance Chemotherapy for Childhood Acute Lymphoblastic Leukemia or Lymphoma

小崎健次郎

Journal of pediatric hematology oncology 30 347-352 2008年

研究論文（学術雑誌）, 共著, 査読有り

Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes

小崎健次郎

Nature Genetics 40 237-242 2008年

研究論文（学術雑誌）, 共著, 査読有り

Split hand foot malformation with whorl-like pigmentary pattern: Phenotypic expression of somatic mosaicism for the p63 mutation.

小崎健次郎

American Journal of Medical Genetics 146 2574 - 2577 2008年

研究論文（学術雑誌）, 共著

単一遺伝子病

小崎健次郎

小児内科 40 1246 - 1249 2008年

研究論文（学術雑誌）, 単著

Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia.

小崎健次郎

Horm Res Paediatr 2007年

研究論文（学術雑誌）, 共著

Access to Document (DOI)

Embryonic expression profile of chicken CHD7, the ortholog of the causative gene for CHARGE syndrome. Birth Defects Reseach Part A

小崎健次郎

Clinical Molecular Teratology 79 50-57 2007年

研究論文（学術雑誌）, 共著, 査読有り

An Alu Retrotransposition-Mediated Deletion of CHD7 in a Patient With CHARGE Syndrome

小崎健次郎

American Journal of Medical Genetics 143 721-726 2007年

研究論文（学術雑誌）, 共著, 査読有り

Monozygotic twins of Smith-Magenis syndrome

小崎健次郎

American Journal of Medical Genetics 143 768-769 2007年

研究論文（学術雑誌）, 共著, 査読有り

EFNB1 mutation at the ephrin ligand - ephrin receptor dimerization interface in a patient with craniofrontonasal syndrome

小崎健次郎

Congenital Anomalies 47 49-52 2007年

研究論文（学術雑誌）, 共著, 査読有り

Partial deletion of LIS1: A pitfall in molecular diagnosis of Miller-Dieker syndrome

小崎健次郎

Pediatric Neurology 36 258-260 2007年

研究論文（学術雑誌）, 共著, 査読有り

Wide phenotypic variations within a family with SALL1 mutations: Isolated external ear abnormalities to Goldenhar syndrome

小崎健次郎

American Journal of Medical Genetics 143 1087-1890 2007年

研究論文（学術雑誌）, 共著, 査読有り

Upper airway obstruction in neonates and infants with CHARGE syndrome

小崎健次郎

American Journal of Medical Genetics 143 1815-1820 2007年

研究論文（学術雑誌）, 共著, 査読有り

Identification of a prosencephalic-specific enhancer of SALL1: Comparative genomic approach using the chick embryo

小崎健次郎

Pediatric Research 61 660-665 2007年

研究論文（学術雑誌）, 共著, 査読有り

Screening for Alagille syndrome mutations in the JAG1 and NOTCH2 genes using denaturing high-performance liquid chromatography

小崎健次郎

Genetic Testing 11 216-227 2007年

研究論文（学術雑誌）, 共著, 査読有り

Multiplex PCR/liquid Chromatography Assay for Screening of Subtelomeric Rearrangements

小崎健次郎

Genetic Testing （Genetic Testing） 11 241-248 2007年

研究論文（学術雑誌）, 共著, 査読有り

Two distinctive mechanisms leading to disruption of the SHOX transcription unit in a single family

小崎健次郎

American Journal of Medical Genetics 143 2838-2842 2007年

研究論文（学術雑誌）, 共著, 査読有り

Diversity of supernumerary tooth formation in siblings with cleidocranial dysplasia having identical mutation in RUNX2: Possible involvement of non-genetic or epigenetic regulation

小崎健次郎

Orthodontics and Craniofacial Research 10 222-225 2007年

研究論文（学術雑誌）, 共著, 査読有り

遺伝子診断を取り巻く最近の動向遺伝子検査ネットワーク

小崎健次郎　沼部博直、松原洋一、小崎健次郎、小杉眞司

臨床検査 51 1621 - 1623 2007年

研究論文（学術雑誌）, 共著

薬効および副作用とその対策　抗てんかん薬

小崎健次郎　吉井聡、高橋孝雄、小崎健次郎、下郷幸子

小児科 47 783 - 788 2006年

研究論文（学術雑誌）, 共著

Molecular Pathology of Shprintzen-Goldberg Syndrome

小崎健次郎

American Journal of Medical Genetics 140 104-108 2006年

研究論文（学術雑誌）, 共著, 査読有り

1173C>T polymorphism in VKORC1 modulates the required warfarin dose.

小崎健次郎

Pediatric Cardiology 27 685-688 2006年

研究論文（学術雑誌）, 共著, 査読有り

Cleidocranial dysplasia plus vascular anomalies with 6p21.2 microdeletion spanning RUNX2 and VEGF

小崎健次郎

American Journal of Medical Genetics 140 398-401 2006年

研究論文（学術雑誌）, 共著, 査読有り

Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma

小崎健次郎

Journal of Pediatric Hematology and Oncology 28 64-68 2006年

研究論文（学術雑誌）, 共著, 査読有り

Phenotypic spectrum of CHARGE syndrome with CHD7 mutations

小崎健次郎

Journal of Pediatrics 148 410-414 2006年

研究論文（学術雑誌）, 共著, 査読有り

Hypothyroidism in Peters plus syndrome

小崎健次郎

Ophthalmic Genetics 27 67-69 2006年

研究論文（学術雑誌）, 共著, 査読有り

Discrepancies in cytogenetic results between amniocytes and postnatally obtained blood: trisomy 9 mosaicism

小崎健次郎

Congenital Amomalies 46 115-117 2006年

研究論文（学術雑誌）, 共著, 査読有り

Paternal gonadal mosaicism of NIPBL mutation in a father of siblings with Cornelia de Lange syndrome

小崎健次郎

Prenatal Diagnosis 26 1054-1057 2006年

研究論文（学術雑誌）, 共著, 査読有り

Genome-wide screening of dioxin-responsive genes in fetal brain: bioinformatic and experimental approaches

小崎健次郎

Congenital Anomalies 46 135-143 2006年

研究論文（学術雑誌）, 共著, 査読有り

Screening for partial deletions of CREBBP locus in Rubinstein-Taybi Syndrome patients using multiplex PCR / Liquid chromatography

小崎健次郎

Genetic Testing 10 265-271 2006年

研究論文（学術雑誌）, 共著, 査読有り

Comprehensive screening of CHD7 mutations among patients with CHARGE Syndrome using denaturing high-performance liquid chromatography

小崎健次郎

Genetic Testing 10 244-251 2006年

研究論文（学術雑誌）, 共著

Kallmann Syndrome phenotype in a female patient with CHARGE syndrome and CHD7 mutation

小崎健次郎

Endocrine Journal 53 741-743 2006年

研究論文（学術雑誌）, 共著, 査読有り

Umbilical cord length in urinary tract abnormalities associated with oligohydramnios: Evidence regarding developmental pathogenesis.

小崎健次郎

Fetal and Pediatric Pathology 25 233-240 2006年

研究論文（学術雑誌）, 共著, 査読有り

Monopolar preparation of human lymphocytes for evaluation of the metaphase chromosome alignment

小崎健次郎

Chromosome Science 9 75-83 2006年

研究論文（学術雑誌）, 共著, 査読有り

低身長(小人症)を伴う遺伝性(先天性)症候群　Russell-Silver症候群

小崎健次郎泉幸佑、長谷川奉延

日本臨床別冊内分泌症候群 III 436 - 439 2006年

研究論文（学術雑誌）, 共著

Deletion involving the TWIST locus and the HOXA cluster: A contiguous gene syndrome on 7p?

小崎健次郎

Congenital Anomalies 45 35-38 2005年

研究論文（学術雑誌）, 共著, 査読有り

Refining chromosomal region critical for Down syndrome-related heart defects with a case of cryptic 21q22.2 duplicatio

小崎健次郎

Congenital Anomalies 45 62-64 2005年

研究論文（学術雑誌）, 共著

Comprehensive screening of the thiopurine methyltransferase polymorphisms by using denaturing high-performance liquid chromatography

小崎健次郎

Genetic Testing 9 85-92 2005年

研究論文（学術雑誌）, 共著, 査読有り

OEIS compelx With del(3)(q12.2q13.2)

小崎健次郎

American Journal of Medical Genetics 135 224-226 2005年

研究論文（学術雑誌）, 共著, 査読有り

Iridic and retinal coloboma associated with prenatal methimazole exposure

小崎健次郎

American Journal of Medical Genetics 139 156-158 2005年

研究論文（学術雑誌）, 共著

Comprehensive screening of CREBBP mutations among patients with Rubinstein-Taybi syndrome using denaturing high-performance liquid chromatography

小崎健次郎

Congenital Anomalies 45 125-131 2005年

研究論文（学術雑誌）, 共著, 査読有り

DHPLC in clinical molecular diagnostic services

小崎健次郎

Molecular Genetics and Metabolism 86 117 - 123 2005年

研究論文（学術雑誌）, 共著

先天異常症候群の遺伝子診断システム

小崎健次郎

小児内科 37 1317 - 1321 2005年

研究論文（学術雑誌）, 単著

患者データベースを用いた臨床実習システム

小崎健次郎　高橋孝雄、小崎健次郎、嶋田博之、三橋隆行

IT活用教育方法研究 8 6 - 10 2005年

研究論文（学術雑誌）, 共著

多発奇形症侯群・染色体異常の遺伝カウンセリング

小崎健次郎　小崎里華、左合治彦、小崎健次郎

小児科 46 939 - 948 2005年

研究論文（学術雑誌）, 共著

多発奇形症候群の遺伝子解析

小崎健次郎　鳥居千春、小崎健次郎

日本臨床 63 （増刊遺伝子診療学） 431 - 436 2005年

研究論文（学術雑誌）, 共著

筋強直性ジストロフィー，神経線維腫症１型およびNoonan症候群の合併例に発生した側弯症の治療経験

小崎健次郎　藤吉兼浩、松本守雄、中村雅也、千葉一裕、戸山芳昭、小崎健次郎

臨床整形外科 39 （ 7 ） 979 - 982 2004年07月

研究論文（学術雑誌）, 共著

Marfanoid Habitus With Abnormal Situs.

Kosaki K ,Bird LM, Maeda J, Higuchi M, Jones MC, Matsumoto M'

American Journal of Medical Genetics 127A （ 3 ） 310-312 2004年06月

研究論文（学術雑誌）, 共著

Somatic PTPN11 mutation with a heterogeneous clonal origin in children with juvenile myelomonocytic leukemia.

Shimada H, Mori T, Shimasaki N, Shimizu K, Takahashi T, Kosaki K

Leukemia 18 （ 6 ） 1142-1144 2004年06月

研究論文（学術雑誌）, 共著

Genitourinary anomaly in congenital varicella syndrome: case report and review.

Fujita H, Yoshii A, Maeda J, Kosaki K, Shishido S, Nakai H, Awazu M

Pediatric Nephrology 19 （ 5 ） 554-557 2004年05月

研究論文（学術雑誌）, 共著

Premature ovarian failure in a female with proximal symphalangism and noggin mutation.

Kosaki K, Sato S, Hasegawa T, Matsuo N, Suzuki T, Ogata T

Fertility and Sterility 81 （ 4 ） 1137-1139 2004年04月

研究論文（学術雑誌）, 共著

Position-specific expression of Hox genes along the gastrointestinal tract.

Yahagi N, Kosaki R, Ito T, Mitsuhashi T, Shimada H, Tomita M, Takahashi T, Kosaki K'

Congenital Anomalies 44 （ 1 ） 18-26 2004年03月

研究論文（学術雑誌）, 共著

EYA1 Mutation in a Newborn Female Presenting with Cardiofacial Syndrome.

Shimasaki N, Watanabe K, Hara M, Kosaki K'

Pediatric Cardiology 25 （ - ） 411-413 2004年

研究論文（学術雑誌）, 共著

Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality.

Kosaki K, Ikeda K, Miyakoshi K, Ueno M, Kosaki R, Takahashi D, Tanaka M, Torikata C, Yoshimura Y, Takahashi T

American Journal of Medical Genetics 129A （ 3 ） 308-311 2004年

研究論文（学術雑誌）, 共著, 査読有り

Broader geographical spectrum of Cohen syndrome due to COH1 mutations.

Mochida GH, Rajab A, Eyaid W, Lu A, Al-Nouri D, Kosaki K, Noruzinia M, Sarda P, Ishihara J, Bodell A, Apse K, Walsh CA

Journal of Medical Genetics 41 （ 6 ） e87 2004年

研究論文（学術雑誌）, 共著, 査読有り

Hyperinsulinemic hypoglucemia in a newborn infant with trisomy 13.

Tamame T, Hori N, Homma H, Yoshida R, Inokuchi M, Kosaki K, Takahashi T, Hasegawa T

American Journal Medical Genetics 129A （ ? ） 321-322 2004年

研究論文（学術雑誌）, 共著

A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam.

小崎健次郎

Brain and Development 26 530-534 2004年

研究論文（学術雑誌）, 共著, 査読有り

Large fontanelles are a shared feature of haploinsufficiency of RUNX2 and its co-activator CBFB.

小崎健次郎

Congenital Anomalies 44 225-229 2004年

研究論文（学術雑誌）, 共著, 査読有り

小児病棟における, インフルエンザ接触者へのオセルタミビル予防内服効果

小崎健次郎　新庄正宜、佐藤清二、菅谷憲夫、三田村敬子、武内可尚、小崎健次郎、高橋孝雄

感染症学雑誌 78 262 - 269 2004年

研究論文（学術雑誌）, 共著

Fluorescence in situ hybridization 法および restriction fragment length polymorphism 法を併用した網膜芽細胞腫の遺伝子診断

小崎健次郎　羽藤晋、井上真、石川薫、野田航介、谷野富彦、真島行彦、小崎健次郎、小口芳久

日本眼科學会雑誌 108 482 - 488 2004年

研究論文（学術雑誌）, 共著

X-linked cubitus valgus with mental retardation and typical face.

Jones KL, Kosaki K, Hall BD

American Journal of Medical Genetics 123A 33-36 2003年11月

研究論文（学術雑誌）, 共著

EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma.

Akahoshi K, Sakazume S, Kosaki K, Ohashi H, Fukushima Y

American Journal of Medical Genetics 120A （ 3 ） 370-373 2003年07月

研究論文（学術雑誌）, 共著

Lymphstasis in a boy with Noonan syndrome: implication for the development of skeletal features.

小崎健次郎

Endocrine Journal 50 （ 3 ） 319-324 2003年06月

研究論文（学術雑誌）, 共著

Micropenis and the 5alpha-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients.

Sasaki Goro, Ogata Tsutomu, Ishii Tomohiro, Kosaki Kenjiro, Sato Seiji, Homma Keiko, Takahashi Takao, Hasegawa Tomonobu, Matsuo Nobutake

Journal of clinical endocrinology and metabolism 88 （ 7 ） 3431 - 3436 2003年

研究論文（学術雑誌）, 共著

胃の前癌病変の遺伝子変化 H. pylori 感染との関連から

小崎健次郎5.　鈴木秀和、安孫子由佳、小崎健次郎、石井裕正

生物物理化学（日本電気泳動学会） 47 85 - 89 2003年

研究論文（学術雑誌）, 共著

小球性低色素性貧血を手がかりとして発見されたサラセミアの一家系

小崎健次郎　島崎紀子、森鉄也、嶋田博之、小崎健次郎、高橋孝雄

小児科臨床 56 1875 - 1879 2003年

研究論文（学術雑誌）, 共著

遺伝学はゲノム情報でどう変わるか ?ポストゲノム時代を展望する

小崎健次郎

遺伝（別冊15 ） 158-164 2002年11月

研究論文（学術雑誌）, 単著

PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.

小崎健次郎

Journal of Clinical Endocrinology and Metabolism 87 （ 8 ） 3529-3533 2002年08月

研究論文（学術雑誌）, 共著

A novel mutation in the FOXL2 gene in a patient with Blepharophimosis syndrome: Differential role of the polyalanine tract in the development of the ovary and the eyelid.

小崎健次郎

Ophthalmic Genetics 23 （ 1 ） 43-47 2002年03月

研究論文（学術雑誌）, 共著

Complete mutation analysis panel of the 39 human HOX genes

Kosaki K, Kosaki R, Suzuki T, Yoshihashi H, Sasaki K, Tomita M, McGinnis W, Matuso N

Teratology 65 （ 2 ） 50-62 2002年02月

研究論文（学術雑誌）, 共著

Characterization of the aryl hydrocarbon receptor repressor gene and association of its Pro185Ala polymorphism with micropenis.

小崎健次郎

Teratology 65 （ 1 ） 10-18 2002年01月

研究論文（学術雑誌）, 共著

Micropenis and the AR Gene: Mutation and CAG Repeat-Length Analysis.

小崎健次郎

Journal of Clinical Endocrinology and Metabolism 86 （ 11 ） 5372-5378 2001年11月

研究論文（学術雑誌）, 共著

A de novo mutation (R279C) in the P63 gene in a patient with EEC syndrome.

小崎健次郎

Clinical Genetics 60 （ 4 ） 314-315 2001年10月

研究論文（学術雑誌）, 共著

Female patient showing hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID).

Kosaki K, Shimasaki N, Fukushima H, Hara M, Ogata T, Matsuo N

American Journal of Human Genetics 69 （ 3 ） 664-666 2001年09月

研究論文（学術雑誌）, 共著

Human homolog of the mouse imprinted gene Impact resides at the pericentric region of chromosome 18 within the critical region for bipolar affective disorder.

小崎健次郎

Molecular Psychiatry 6 （ 1 ） 87-91 2001年06月

研究論文（学術雑誌）, 共著

Mutation analysis of left-right axis determining genes in NOD and ICR, strains susceptible to maternal diabetes.

小崎健次郎

Teratology 63 （ 3 ） 119-126 2001年03月

研究論文（学術雑誌）, 共著

Fluorescence-based DHPLC for allelic quantification by single-nucleotide primer extension.

小崎健次郎

Journal of Biochemical and Biophysical Methods 47 （ 1-2 ） 111-119 2001年01月

研究論文（学術雑誌）, 共著

核内転写因子の遺伝子異常による多発性奇形症候群

小崎健次郎

THE BONE 15681 - 15683 2001年

研究論文（学術雑誌）, 単著

Reply to Mergenthaler et al.

小崎健次郎

American Journal of Human Genetics 68 544-546 2001年

研究論文（学術雑誌）, 共著

免疫不全を伴う短肢型小人症

小崎健次郎小崎健次郎,　吉橋博史

免疫不全症候群（下巻）日本臨床領域別症候群シリーズ 32 574-575 2001年

研究論文（学術雑誌）, 共著

Dermal hypoplasia, focal

小崎健次郎小崎健次郎,　吉橋博史

先天異常症候群事典（上巻）日本臨床領域別症候群シリーズ 33 545-547 2001年

研究論文（学術雑誌）, 共著

Russell-Silver症候群　染色体・奇形　

小崎健次郎小崎健次郎,　吉橋博史

小児科診療「小児の症候群」 64 （増刊） 57 2001年

研究論文（学術雑誌）, 共著

【成長障害】　最新のトピックス　Russell-Silver症候群　第7番染色体母性片親性ダイソミーをめぐる話題

Kosaki Kenjirou，Yoshihashi Hiroshi

小児科診療 64 911-914 2001年

研究論文（学術雑誌）, 共著

小児の症候群　新生児　IUGR(子宮内発育遅延)

吉橋博史，小崎健次郎

小児科診療 64 （増刊号） 435 2001年

研究論文（学術雑誌）, 共著

染色体・奇形　Townes-Brocks症候群

土橋隆俊，小崎健次郎

小児科診療増刊号（小児の症候群） 64 2001年

研究論文（学術雑誌）, 共著

免疫不全を伴う短肢型小人症

小崎健次郎，吉橋博史

別冊日本臨床　領域別症候群シリーズ * （ 32 ） 324-326 2000年12月

研究論文（学術雑誌）, 共著

左右軸を決定する遺伝子

小崎健次郎

小児科診療 63 （ 12 ） 2152-2153 2000年12月

研究論文（学術雑誌）, 単著

Diagnosis of maternal uniparental disomy of chromosome 7 with a methylation specific PCR assay.

小崎健次郎

Journal of Medical Genetics, 37 （ E19 ） 2000年09月

研究論文（学術雑誌）, 共著

Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome.

小崎健次郎

American Journal of Human Genetics 67 （ 2 ） 476-482 2000年08月

研究論文（学術雑誌）, 共著

Mother and daughter with 45,X/46,X,r(X)(p22.3q28) and mental retardation: Analysis of the X-inactivation patterns

Matsuo Mari, Muroya Koji, Nanao Kenji, Hasegawa Yukihiro, Kosaki Kenjiro, Ogata Tsutomu

American Journal of Medical Genetics 91 （ 4 ） 267-272 2000年04月

研究論文（学術雑誌）, 共著

Isoform-specific imprinting of the human PEG1/MEST gene.

小崎健次郎

American Journal of Human Genetics 66 309-312 2000年

研究論文（学術雑誌）, 共著

内分泌攪乱物質は中枢機能に影響するか

小崎健次郎

ホルモンと臨床 47 （ 12 ） 1173-1177 1999年12月

研究論文（学術雑誌）, 単著

Random X-inactivation in a girl with duplication Xp11.2-p21.3:report of a patient and review of the literature.

Matsuo Nobutake, Muroya kouji, Kosaki kenjirou, IshiiTomohiro, Fukushima Hiroyuki, Anzo Makoto, Ogata Tsutomu

American Journal of Medical Genetics 86 （ 1 ） 44-50 1999年09月

研究論文（学術雑誌）, 共著

Developmental delay in fetal aminopterin/methotrexate syndrome

Campo del Miguel, Kosaki Kenjiro, Jones Kenneth

Teratology 60 （ 10 ） 10-12 1999年07月

研究論文（学術雑誌）, 共著

形態異常診断法: dysmorphology

小崎里華，小崎健次郎

臨床医 25 （ 6 ） 1211-1214 1999年06月

研究論文（学術雑誌）, 共著

糖尿病母体児の奇形の実態と研究の展望

小崎健次郎，前山克博

Diabetes Frontier 10 （ 5 ） 690-694 1999年05月

研究論文（学術雑誌）, 共著

左右を決定する遺伝子

小崎健次郎小崎里華,　小崎健次郎

小児科の進歩 19 （ 1 ） 116-118 1999年04月

研究論文（学術雑誌）, 共著

Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development.

Kosaki Kenjiro, Bassi Maria-Teressa, Kosaki Rika, Lewin Mike, Belmont John, Schauer G, Casey Brett1

American Journal of Human Genetics 64 （ 3 ） 712-721 1999年03月

研究論文（学術雑誌）, 共著

Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB.

Kosaki Rika, Gebbia Marinella, Kosaki Kenjiro, Lewin Mike, Bowers Peter, Towbin Jeff, Casey Bertt

American Journal of Medical Genetics 82 （ 1 ） 70-76 1999年01月

研究論文（学術雑誌）, 共著

Enhanced DNA fragmentation in the thymus of spontaneously hypertensive rats.

小崎健次郎

American Journal of Physiology 276 （ 6 Pt 2 ） H2135-40 1999年01月

研究論文（学術雑誌）, 共著

Genetics of human left-right axis malformations.

小崎健次郎

Seminars in Cell and Developmental Biology 9 （ 1 ） 89-99 1998年02月

研究論文（学術雑誌）, 共著

fetal alcohol syndrome (胎児アルコール症候群

小崎健次郎小崎健次郎,　小崎里華

診断と治療 86 （増刊） 769 1998年

研究論文（学術雑誌）, 共著

Fetal hydantoin syndrome (胎児ヒダントイン症候群)

小崎健次郎小崎健次郎,　小崎里華

診断と治療 86 （増刊） 770 1998年

研究論文（学術雑誌）, 共著

Fetal valproate syndrome (胎児バルプロ酸症候群)

小崎健次郎小崎健次郎,　小崎里華

診断と治療 86 （増刊） 771 1998年

研究論文（学術雑誌）, 共著

Ritscher-Schinzel (3C) syndrome: Documentation of the phenotype.

小崎健次郎

American Journal of Medical Genetics 68 （ 4 ） 421-427 1997年02月

研究論文（学術雑誌）, 共著

Prader-Willi syndrome and Angelman syndrome: Diagnosis with a bisulfite treated-methylation specific PCR method.

小崎健次郎

American Journal of Medical Genetics 73 308-313 1997年

研究論文（学術雑誌）, 共著

Parametric imaging of the chick embryonic cardiovascular system

小崎健次郎

A novel functional measure.Pediatric Research 41 451-456 1997年

研究論文（学術雑誌）, 共著

Zimmer phocomelia: Delineation by principal coordinate analysis.

小崎健次郎

American Journal of Medical Genetics 66 （ 1 ） 55-59 1996年12月

研究論文（学術雑誌）, 共著

Cervical flexure: Its contribution to normal and abnormal cardiac morphogenesis.

小崎健次郎

Teratology 54 （ 3 ） 135-144 1996年09月

研究論文（学術雑誌）, 共著

Dysmorphologyの系統的アプローチ

小崎健次郎小崎健次郎

小児科診療 59 1739-1744 1996年

研究論文（学術雑誌）, 単著

Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: Does abnormal cholesterol metabolism affect the function of Sonic Hedgehog?

小崎健次郎

American Journal of Medical Genetics 66 478-484 1996年

研究論文（学術雑誌）, 共著

Isolated aplasia of the anterior pituitary as a cause of congenital hypopituitarism.

小崎健次郎

Hormone Research 35 （ 6 ） 226-228 1991年

研究論文（学術雑誌）, 共著

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