研究者詳細 - 小崎　健次郎

論文 - 小崎　健次郎

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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

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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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小崎 健次郎

論文 - 小崎 健次郎

小崎　健次郎

論文 - 小崎　健次郎