論文 - 小崎　健次郎

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

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© 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

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© 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

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© 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

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© 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

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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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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

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© 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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