Publications by authors named "Hiroshi Yoshihashi"

34 Publications

Recurrent NFIA K125E substitution represents a loss-of-function allele: Sensitive in vitro and in vivo assays for nontruncating alleles.

Am J Med Genet A 2021 Jul 11;185(7):2084-2093. Epub 2021 May 11.

Advanced Insect Research Promotion Center, Kyoto Institute of Technology, Kyoto, Japan.

Nuclear factor I A (NFIA) is a transcription factor that belongs to the NFI family. Truncating variants or intragenic deletion of the NFIA gene are known to cause the human neurodevelopmental disorder known as NFIA-related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the NFIA-related disorder who shared a missense variant p.Lys125Glu (K125E) in the NFIA gene. Patient 1 was a 6-year-old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14-month-old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild-type human NFIA in Drosophila caused developmental defects such as eye malformation and premature death, while that of human NFIA K125E variant allele did not. nfia-deficient zebrafish embryos showed defects of midline-crossing axons in the midbrain/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild-type human NFIA, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of HES1 promoter in cultured cells. Taken together, we concluded that the K125E variant in the NFIA gene is a loss-of-function mutation.
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http://dx.doi.org/10.1002/ajmg.a.62226DOI Listing
July 2021

Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.

Am J Med Genet A 2021 03 27;185(3):884-888. Epub 2020 Dec 27.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

We report a male adult with early infantile-onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2-related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large-scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.
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http://dx.doi.org/10.1002/ajmg.a.62020DOI Listing
March 2021

Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.

Sci Rep 2020 10 16;10(1):17575. Epub 2020 Oct 16.

Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.

Cyclin-dependent kinase 8 (CDK8) is a member of the CDK/Cyclin module of the mediator complex. A recent study reported that heterozygous missense CDK8 mutations cause a neurodevelopmental disorder in humans. The mechanistic basis of CDK8-related disorder has yet to be delineated. Here, we report 2 patients with de novo missense mutations within the kinase domain of CDK8 along with the results of in vitro and in vivo functional analyses using a zebrafish model. Patient 1 and Patient 2 had intellectual disabilities and congenital anomalies. Exome analyses showed that patient 1 had a heterozygous de novo missense p.G28A variant in the CDK8 (NM_001260.3) gene and patient 2 had a heterozygous de novo missense p.N156S variant in the CDK8 gene. We assessed the pathogenicity of these two variants using cultured-cells and zebrafish model. An in vitro kinase assay of human CDK8 showed that enzymes with a p.G28A or p.N156S substitution showed decreased kinase activity. An in vivo assays of zebrafish overexpression analyses also showed that the p.G28A and p.N156S alleles were hypomorphic alleles. Importantly, the inhibition of CDK8 kinase activity in zebrafish embryos using a specific chemical inhibitor induced craniofacial and heart defects similar to the patients' phenotype. Taken together, zebrafish studies showed that non-synonymous variants in the kinase domain of CDK8 act as hypomorphic alleles causing human congenital disorder.
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http://dx.doi.org/10.1038/s41598-020-74642-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567849PMC
October 2020

Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome.

Am J Med Genet A 2020 10 17;182(10):2333-2344. Epub 2020 Aug 17.

Genetic Counseling Program, Graduate School of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Japan.

Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000-8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.
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http://dx.doi.org/10.1002/ajmg.a.61793DOI Listing
October 2020

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan.

J Hum Genet 2020 Dec 13;65(12):1045-1053. Epub 2020 Jul 13.

Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan.

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.
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http://dx.doi.org/10.1038/s10038-020-0802-2DOI Listing
December 2020

White matter abnormality in Jacobsen syndrome assessed by serial MRI.

Brain Dev 2020 Sep 5;42(8):621-625. Epub 2020 Jun 5.

Department of Neurology, Tokyo Metropolitan Children's Medical Center, Japan.

Introduction: Jacobsen syndrome (JS) is caused by a deletion at the terminus of the long arm of chromosome 11. There are few reports of JS associated with cerebral white matter abnormalities (WMA), and the etiology, pathophysiology, and time-dependent changes in WMA with JS still remain unclear.

Case Report: The patient was a 2-month-old female with several morphological anomalies, including trigonocephaly, ectropion, flat nasal bridge, low-set ears, and sparse eyebrows. Chromosome analysis (G-banding karyotyping) of 46,XX,del(11)(q23.3) led to the diagnosis of JS. Head MRI performed at age 9 months indicated diffuse WMA with hyperintense signals on T2-weighted imaging. MRI at age 2.5 years demonstrated a decrease in the WMA and progressive myelination.

Discussion: These findings suggested that the WMA in the present patient were due to chronic white matter edema associated with a deletion in the 11q terminal region of HEPACAM/GlialCAM, a causative gene for megalencephalic leukoencephalopathy with subcortical cysts type 2B (MLC2B). As with some of MLC2B patients, the WMA in the present patient improved over time. The present report is the first to document dramatic changes in WMA in JS visualized by serial MRI examinations from the neonatal period through early childhood.

Conclusion: The findings of the present study suggested that WMA in JS are due to chronic white matter edema associated with HEPACAM/GlialCAM deletion and show gradual improvement over time, as seen in some MLC2B patients.
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http://dx.doi.org/10.1016/j.braindev.2020.05.001DOI Listing
September 2020

The Prevalence and Clinical Characteristics of -Associated Autosomal Dominant Hearing Loss.

Genes (Basel) 2019 09 24;10(10). Epub 2019 Sep 24.

Department of Otorhinolaryngology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

is well known as a causative gene for autosomal dominant mid-frequency hearing loss observed in various populations. In this study, we performed next-generation sequencing analysis of a large Japanese hearing loss cohort, including eight hundred and twelve (812) subjects from unrelated autosomal dominant hearing loss families, to estimate the prevalence and phenotype-genotype correlations in patients with mutations. The prevalence of mutations in Japanese autosomal dominant sensorineural hearing loss families was found to be 3.2%. With regard to the type of hearing loss, the patients with mutations in the nidogen-like domain or ZA domain of showed varied audiograms. However, most of the patients with mutations in the ZP domain showed mid-frequency hearing loss. The rate of hearing deterioration in -associated hearing loss patients and in the normal hearing Japanese control population were the same and regression lines for each group were parallel. We carried out haplotype analysis for four families which had one recurring missense variant, c.5597C>T (p.Thr1866Met). Our results revealed four different haplotypes, suggesting that this mutation occurred independently in each family. In conclusion, variants represent the second largest cause of autosomal dominant sensorineural hearing loss in Japan. The hearing loss progression observed in the patients with mutations might reflect presbycusis. The c.5597C>T mutation occurred in a mutational hot spot and is observed in many ethnic populations.
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http://dx.doi.org/10.3390/genes10100744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826443PMC
September 2019

IGF2 Mutations.

J Clin Endocrinol Metab 2020 01;105(1)

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Objective: IGF2 is a paternally expressed growth-promoting gene. Here, we report five cases with IGF2 mutations and review IGF2 mutation-positive patients described in the literature. We also compare clinical features between patients with IGF2 mutations and those with H19/IGF2:IG-DMR epimutations.

Results: We recruited five cases with IGF2 mutations: case 1 with a splice site mutation (c.-6-1G>C) leading to skipping of exon 2 and cases 2-5 with different missense mutations (p.(Cys70Tyr), p.(Cys71Arg), p.(Cys33Ser), and p.(Cys45Ser)) affecting cysteine residues involved in the S-S bindings. All the mutations resided on the paternally inherited allele, and the mutation of case 5 was present in a mosaic condition. Clinical assessment revealed Silver-Russell syndrome (SRS) phenotype with Netchine-Harbison scores of ≥5/6 in all the apparently nonmosaic 14 patients with IGF2 mutations (cases 1-4 described in this study and 10 patients reported in the literature). Furthermore, compared with H19/IGF2:IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index, and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values.

Conclusions: This study indicates that IGF2 mutations constitute a rare but important cause of SRS. Furthermore, while both IGF2 mutations and H19/IGF2:IG-DMR epimutations lead to SRS, a certain degree of phenotypic difference is observed between the two groups, probably due to the different IGF2 expression pattern in target tissues.
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http://dx.doi.org/10.1210/clinem/dgz034DOI Listing
January 2020

Attitudes of clinical geneticists and certified genetic counselors to genome editing and its clinical applications: A nation-wide questionnaire survey in Japan.

J Hum Genet 2019 Sep 5;64(9):945-954. Epub 2019 Jul 5.

Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan.

Genome editing of the human embryo using CRISPR/Cas9 has the potential to prevent hereditary diseases from being transmitted to the next generation. However, attitudes to this technology have not been examined sufficiently among the genetic professionals who will use it in the near future. We conducted a questionnaire survey of Japanese clinical geneticists and certified genetic counselors. Differences were observed between them in their recognition of this technology and impressions on its difficulty and cost. Both groups worried about misuse of it, with insufficient information and rules. As key elements for such rules, they considered ethics, safety, and purpose. Most disapproved of modifying physical traits as an enhancement, though they hoped for the treatment of severe diseases. At current clinical sites, they tended to adopt a prudent attitude by mentioning only the possibility of genome editing in the future. Academic policies and legislation are required, especially for application in human embryos, through a consensus of professionals and general citizens. Furthermore, professionals should maintain awareness of new developments and regularly reexamine attitudes for the ongoing development of more suitable rules, education systems, and clinical protocols. As preparation for changes, opportunities to address ethical issues and initiate discussions are also required.
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http://dx.doi.org/10.1038/s10038-019-0635-zDOI Listing
September 2019

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

Am J Med Genet A 2019 08 7;179(8):1628-1630. Epub 2019 Jun 7.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

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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http://dx.doi.org/10.1002/ajmg.a.61261DOI Listing
August 2019

SATB2-associated syndrome in patients from Japan: Linguistic profiles.

Am J Med Genet A 2019 06 7;179(6):896-899. Epub 2019 Mar 7.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

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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http://dx.doi.org/10.1002/ajmg.a.61114DOI Listing
June 2019

An association with hypopituitarism and 9q subtelomere deletion syndrome.

Clin Case Rep 2018 Dec 25;6(12):2371-2375. Epub 2018 Oct 25.

Department of Pediatrics Keio University School of Medicine Tokyo Japan.

Hypopituitarism could have been overlooked so far in the patients with 9q subtelomere deletion syndrome (9qSTDS); thus, further investigations or reevaluation of clinical information, especially hormonal evaluations, are warranted to determine whether hypopituitarism is a rare or relatively common presentation in patients with 9qSTDS.
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http://dx.doi.org/10.1002/ccr3.1591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293262PMC
December 2018

Three patients with DeSanto-Shinawi syndrome: Further phenotypic delineation.

Am J Med Genet A 2018 06 16;176(6):1335-1340. Epub 2018 Apr 16.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

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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http://dx.doi.org/10.1002/ajmg.a.38703DOI Listing
June 2018

Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica.

Eur J Med Genet 2017 Dec 12;60(12):635-638. Epub 2017 Aug 12.

Department of Medical Genetics, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient. The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans.
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http://dx.doi.org/10.1016/j.ejmg.2017.08.002DOI Listing
December 2017

Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype.

Am J Med Genet A 2017 May 4;173(5):1353-1357. Epub 2017 Apr 4.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel-Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel-Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen.
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http://dx.doi.org/10.1002/ajmg.a.38167DOI Listing
May 2017

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

Am J Med Genet A 2016 12 11;170(12):3249-3252. Epub 2016 Aug 11.

Department of Neurology, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.

Mutations in the BAF complex (mammalian SWI/SNF complex) are responsible for Coffin-Siris syndrome, which is characterized by developmental delay, distinctive facial features, hirsutism, and hypoplasia/aplasia of the fifth finger/fingernails. Hirschsprung disease is characterized by defective stem cells in the enteric neural system, and the involvement of multiple signaling cascades has been implicated. So far, the roles of the BAF complex in the genesis of Hirschsprung disease have remained unknown. Here, we document a patient with coarse facial features, postnatal growth failure, developmental delay, epilepsy, and hypoplasia of the corpus callosum and cerebellum but without a hypoplastic fifth finger/fingernail. In addition, he had Hirschsprung disease. Exome sequencing with a gene set representing a total of 4,813 genes with known relationships to human diseases revealed a heterozygous frameshift mutation in ARID1B (c.5789delC p.Pro1930Leufs*44). The presence of a congenital cataract and Hirschsprung disease in the presently reported patient further expands the phenotypic spectrum of patients with ARID1B mutations and may suggest the potential role of the BAF complex in the pathogenesis of the enteric neural system. The present observation is in agreement with a recent study of Drosophila neuroblasts showing that the dysregulated BAF complex leads to an abnormal lineage progression of neural stem cell lineages and that Hirschsprung disease is caused by abnormal stem cell lineages in the peripheral neural tissues. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37861DOI Listing
December 2016

A case with neonatal hyperinsulinemic hypoglycemia: It is a characteristic complication of Sotos syndrome.

Am J Med Genet A 2015 May 25;167A(5):1171-4. Epub 2015 Feb 25.

Division of Genetic Research, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis.
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http://dx.doi.org/10.1002/ajmg.a.36996DOI Listing
May 2015

Japanese founder duplications/triplications involving BHLHA9 are associated with split-hand/foot malformation with or without long bone deficiency and Gollop-Wolfgang complex.

Orphanet J Rare Dis 2014 Oct 21;9:125. Epub 2014 Oct 21.

Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.

Background: Limb malformations are rare disorders with high genetic heterogeneity. Although multiple genes/loci have been identified in limb malformations, underlying genetic factors still remain to be determined in most patients.

Methods: This study consisted of 51 Japanese families with split-hand/foot malformation (SHFM), SHFM with long bone deficiency (SHFLD) usually affecting the tibia, or Gollop-Wolfgang complex (GWC) characterized by SHFM and femoral bifurcation. Genetic studies included genomewide array comparative genomic hybridization and exome sequencing, together with standard molecular analyses.

Results: We identified duplications/triplications of a 210,050 bp segment containing BHLHA9 in 29 SHFM patients, 11 SHFLD patients, two GWC patients, and 22 clinically normal relatives from 27 of the 51 families examined, as well as in 2 of 1,000 Japanese controls. Families with SHFLD- and/or GWC-positive patients were more frequent in triplications than in duplications. The fusion point was identical in all the duplications/triplications and was associated with a 4 bp microhomology. There was no sequence homology around the two breakpoints, whereas rearrangement-associated motifs were abundant around one breakpoint. The rs3951819-D17S1174 haplotype patterns were variable on the duplicated/triplicated segments. No discernible genetic alteration specific to patients was detected within or around BHLHA9, in the known causative SHFM genes, or in the exome.

Conclusions: These results indicate that BHLHA9 overdosage constitutes the most frequent susceptibility factor, with a dosage effect, for a range of limb malformations at least in Japan. Notably, this is the first study revealing the underlying genetic factor for the development of GWC, and demonstrating the presence of triplications involving BHLHA9. It is inferred that a Japanese founder duplication was generated through a replication-based mechanism and underwent subsequent triplication and haplotype modification through recombination-based mechanisms, and that the duplications/triplications with various haplotypes were widely spread in Japan primarily via clinically normal carriers and identified via manifesting patients. Furthermore, genotype-phenotype analyses of patients reported in this study and the previous studies imply that clinical variability is ascribed to multiple factors including the size of duplications/triplications as a critical factor.
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http://dx.doi.org/10.1186/s13023-014-0125-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205278PMC
October 2014

Clinical utility of an array comparative genomic hybridization analysis for Williams syndrome.

Congenit Anom (Kyoto) 2014 Nov;54(4):225-7

Department of Child Psychiatry, Komagino Hospital, Tokyo, Japan; Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

To reveal the relation between intellectual disability and the deleted intervals in Williams syndrome, we performed an array comparative genomic hybridization analysis and standardized developmental testing for 11 patients diagnosed as having Williams syndrome based on fluorescent in situ hybridization testing. One patient had a large 4.2-Mb deletion spanning distally beyond the common 1.5-Mb intervals observed in 10/11 patients. We formulated a linear equation describing the developmental age of the 10 patients with the common deletion; the developmental age of the patient with the 4.2-Mb deletion was significantly below the expectation (developmental age = 0.51 × chronological age). The large deletion may account for the severe intellectual disability; therefore, the use of array comparative genomic hybridization may provide practical information regarding individuals with Williams syndrome.
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http://dx.doi.org/10.1111/cga.12065DOI Listing
November 2014

Vesiculopustular eruption in neonate with trisomy 21 and transient myeloproliferative disorder.

J Pediatr 2013 Mar 7;162(3):643-4. Epub 2012 Dec 7.

Department of Dermatology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.jpeds.2012.10.053DOI Listing
March 2013

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

Am J Med Genet A 2012 Oct 10;158A(10):2537-41. Epub 2012 Aug 10.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity. An X-linked recessive mode of transmission has been suggested for this condition based on the observation that male patients have preferentially been affected. Thus far, no candidate genes have been suggested on the X chromosome. We report a male patient with a full-blown Hartsfield syndrome phenotype who had microduplication at Xq24 involving four genes. He presented with bilateral ectrodactyly of the hands (both hands had four fingers with a deep gap between the 2nd and 3rd digits), cleft lip and palate, and a depressed nasal bridge. Magnetic resonance imaging of the brain revealed lobar holoprosencephaly. His G-banded karyotype was normal. Array comparative genomic hybridization (CGH) using the Agilent 244K Whole Human Genome CGH array revealed a microduplication at Xq24 of 210 kb. Parental testing revealed that the deletion was derived from the asymptomatic mother. Of the genes on the duplicated interval, the duplications of SLC25A43 and SLC25A5 appeared to be the most likely to explain the patient's phenotype. From a clinical standpoint, it is important to point out that the propositus, who performs relatively well with holoprosencephaly and has a developmental quotient around 70, has survived multiple life-threatening episodes of hypernatremia. Awareness of the risk of hypernatremia is of great importance for the anticipatory management of patients with ectrodactyly and an oral cleft, even in the absence of overt hypotelorism.
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http://dx.doi.org/10.1002/ajmg.a.35465DOI Listing
October 2012

Congenital corneal staphyloma as a complication of Kabuki syndrome.

Am J Med Genet A 2012 Aug 11;158A(8):2000-2. Epub 2012 Jul 11.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Kabuki syndrome has long been clinically defined based mainly on its characteristic eye features. The recent discovery of MLL2 as a causative gene of Kabuki syndrome has enabled the extreme end of the phenotype to be explored. We herein report on two patients with striking visible congenital staphyloma at birth. A diagnosis of Kabuki syndrome was subsequently made in both patients based on a constellation of characteristic eye features, cardiac abnormalities and severe developmental delay, and finally by the confirmation of MLL2 mutations. In conclusion, congenital corneal staphyloma is a complication of Kabuki syndrome with MLL2 mutations.
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http://dx.doi.org/10.1002/ajmg.a.35453DOI Listing
August 2012

The incidence of hypoplasia of the corpus callosum in patients with dup (X)(q28) involving MECP2 is associated with the location of distal breakpoints.

Am J Med Genet A 2012 Jun 23;158A(6):1292-303. Epub 2012 Apr 23.

Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Duplications of Xq28 harboring the methyl CpG binding protein 2 (MECP2) gene explain approximately 1% of X-linked intellectual disability (XLID). The common clinical features observed in patients with dup(X)(q28) are severe ID, infantile hypotonia, mild dysmorphic features and a history of recurrent infections, and MECP2 duplication syndrome is now recognized as a clinical entity. While some patients with this syndrome have other characteristic phenotypes, the reason for the spectrum of phenotypes has not been clarified. Since dup(X)(q28) rearrangements vary in size and location, genes other than MECP2 might affect the phenotype. We used a high-density oligonucleotide array to carry out precise mapping in eight Japanese families in which dup(X)(q28) was detected using an in-house bacterial artificial chromosome-based microarray to screen cohorts of individuals with multiple congenital anomalies and intellectual disability (MCA/ID) or with XLID. We hypothesized that the size, gene content, and location of dup(X)(q28) may contribute to variable expressively observed in MECP2 duplication syndrome. Genotype-phenotype correlation in our cases together with cases reported in the literature suggested that copy-number gains between two low copy repeats (LCRK1 and LCRL1) are associated with the incidence of hypoplasia of the corpus callosum. Further studies are necessary to understand the mechanism of this association.
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http://dx.doi.org/10.1002/ajmg.a.35321DOI Listing
June 2012

Proportion of malformations and genetic disorders among cases encountered at a high-care unit in a children's hospital.

Eur J Pediatr 2012 Feb 16;171(2):301-5. Epub 2011 Jul 16.

Division of Medical Genetics, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa, Minami-ward, Yokohama 232-8555, Japan.

Genetic disorders and birth defects account for a high percentage of the admissions in children's hospitals. Congenital malformations and chromosomal abnormalities are the most common causes of infant mortality. So their effects pose serious problems for perinatal health care in Japan, where the infant mortality is very low. This paper describes the reasons for admissions and hospitalization at the high-care unit (HCU) of a major tertiary children's referral center in Japan. We retrospectively reviewed 900 admission charts for the period 2007-2008 and found that genetic disorders and malformations accounted for a significant proportion of the cases requiring admission to the HCU. Further, the rate of recurrent admission was higher for patients with genetic disorders and malformations than for those with acquired, non-genetic conditions. Over the past 30 years, admissions attributed to genetic disorders and malformations has consistently impacted on children's hospital and patients with genetic disorders and malformations form a large part of this facility. These results reflect improvements in medical care for patients with genetic disorders and malformations and further highlight the large proportion of cases with genetic disorders, for which highly specialized management is required. Moreover, this study emphasizes the need for involvement of clinical geneticists in HCUs at children's hospitals.
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http://dx.doi.org/10.1007/s00431-011-1534-2DOI Listing
February 2012

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

Pediatr Dermatol 2011 Sep-Oct;28(5):550-4. Epub 2010 Dec 7.

Division of Medical Genetics, Tokyo Metropolitan Children's Hospital, Gunma Children's Medical Center Department of Pediatrics, Keio University School of Medicine, Keio University School of Medicine, Tokyo, Japan.

We report a 46,XY boy with a mild focal dermal hypoplasia phenotype who had both wild-type and mutated copies of the PORCN gene and was, therefore, mosaic for the mutation. He had cutaneous syndactyly, hydronephrosis, and nail dystrophy. Small whitish depigmented spots, which were slightly depressed from the skin surface, were distributed linearly on the trunk and arms. Aside from these findings, streaks of brown-pigmented macules were seen on the dorsal aspect of the legs. Both the linear arrangement of the whitish spots and the streaks of pigmented macules followed the lines of Blaschko. The phenotype of the patient, who did not exhibit cribriform atrophy, telangiectasia or fat herniation, seemed to be much milder than that of typical female patients with focal dermal hypoplasia. Analysis of the genomic DNA extracted from the peripheral lymphocytes revealed a transition 129G>A within exon 1 of PORCN, which leads to a nonsense mutation W43X. The percentage of peripheral lymphocytes carrying a mutation was estimated to be 50% by the subcloning and sequencing of individual clones of the PCR product amplified across the mutation. This patient's case history provides further molecular evidence supporting the concept that "male focal dermal hypoplasia" does exist and that typical features such as telangiectasia and fat herniation are sometimes absent.
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http://dx.doi.org/10.1111/j.1525-1470.2010.01209.xDOI Listing
February 2012

Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies.

J Hum Genet 2011 Feb 28;56(2):110-24. Epub 2010 Oct 28.

Department of Molecular Cytogenetics, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.

Recent advances in the analysis of patients with congenital abnormalities using array-based comparative genome hybridization (aCGH) have uncovered two types of genomic copy-number variants (CNVs); pathogenic CNVs (pCNVs) relevant to congenital disorders and benign CNVs observed also in healthy populations, complicating the screening of disease-associated alterations by aCGH. To apply the aCGH technique to the diagnosis as well as investigation of multiple congenital anomalies and mental retardation (MCA/MR), we constructed a consortium with 23 medical institutes and hospitals in Japan, and recruited 536 patients with clinically uncharacterized MCA/MR, whose karyotypes were normal according to conventional cytogenetics, for two-stage screening using two types of bacterial artificial chromosome-based microarray. The first screening using a targeted array detected pCNV in 54 of 536 cases (10.1%), whereas the second screening of the 349 cases negative in the first screening using a genome-wide high-density array at intervals of approximately 0.7 Mb detected pCNVs in 48 cases (13.8%), including pCNVs relevant to recently established microdeletion or microduplication syndromes, CNVs containing pathogenic genes and recurrent CNVs containing the same region among different patients. The results show the efficient application of aCGH in the clinical setting.
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http://dx.doi.org/10.1038/jhg.2010.129DOI Listing
February 2011

1p36 deletion syndrome associated with Prader-Willi-like phenotype.

Pediatr Int 2010 Aug;52(4):547-50

Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.

Background: 1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes, characterized by moderate to severe mental retardation, characteristic facial appearance, hypotonia, obesity, and seizures. The clinical features often overlap with those of Prader-Willi syndrome (PWS). To elucidate the phenotype-genotype correlation in 1p36 deletion syndrome, two cases involving a PWS-like phenotype were analyzed on molecular cytogenetics.

Methods: Two patients presenting with the PWS-like phenotype but having negative results for PWS underwent fluorescence in situ hybridization (FISH). The size of the chromosome 1p36 deletions was characterized using probes of BAC clones based on the University of California, Santa Cruz (UCSC) Genome Browser.

Results: PWS was excluded on FISH and methylation-specific polymerase chain reaction. Subsequent FISH using the probe D1Z2 showed deletion of the 1p36.3 region, confirming the diagnosis of 1p36 deletion syndrome. Further analysis characterized the 1p36 deletions as being located between 4.17 and 4.36 Mb in patient 1 and between 4.89 and 6.09 Mb in patient 2.

Conclusion: Patients with 1p36 deletion syndrome exhibit a PWS-like phenotype and are therefore probably underdiagnosed. The possible involvement of the terminal 4 Mb region of chromosome 1p36 in the PWS-like phenotype is hypothesized.
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http://dx.doi.org/10.1111/j.1442-200X.2010.03090.xDOI Listing
August 2010

Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature.

Congenit Anom (Kyoto) 2009 Mar;49(1):8-14

Department of Genetic Counseling, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.

Basal cell nevus syndrome (BCNS; Gorlin syndrome) is an autosomal dominant disorder, characterized by a predisposition to neoplasms and developmental abnormalities. BCNS is caused by mutations in the human homolog of the Drosophila patched gene-1, PTCH1, which is mapped on chromosome 9q22.3. Nonsense, frameshift, in-frame deletions, splice-site, and missense mutations have been found in the syndrome. Haploinsufficiency of PTCH1, which is caused by interstitial deletion of 9q22.3, is also responsible for the syndrome. To date, 19 cases with interstitial deletion of long arm of chromosome 9 involving the region of q22 have been reported. We describe two unrelated patients with some typical features of BCNS associated with deletion of 9q21.33-q31.1 and determined the boundary of the deletion by fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones. The results showed that the size of deletions is between 15.33 and 16.04 Mb in patient 1 and between 18.08 and 18.54 Mb in patient 2. Although the size and breakpoints were different from those of previously reported cases, the clinical features are common to patients with 9q22 deletion associated with BCNS. Delineation of the 9q22 deletions and further consideration of the genes responsible for the characteristic manifestations may provide insight into this newly recognized deletion syndrome.
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http://dx.doi.org/10.1111/j.1741-4520.2008.00212.xDOI Listing
March 2009

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

Genet Test 2007 ;11(3):216-27

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Mutations in the JAG1 gene and the NOTCH2 gene cause Alagille syndrome. At present, however, genetic testing of Alagille syndrome is not commonly applied in clinical settings because the currently available assays are technically and financially demanding, mainly because of the size of the genes. In the present study, we optimized the highly sensitive and specific mutation scanning method automated denaturing high-performance liquid chromatography (DHPLC) to analyze the entire coding region of JAG1 and NOTCH2. The coding region was amplified by 69 primer pairs, all of which have the same cycling conditions, aliquoted on a 96-well format PCR plate. In this manner, all the exons were simultaneously amplified using a single block in a thermal cycler. We then wrote a computer script to analyze each segment of JAG1 and NOTCH2 by DHPLC in a serial manner using conditions that were optimized for each amplicon. The implementation of this screening method for JAG1 and NOTCH2 will help medical geneticists confirm their clinical impressions and provide accurate genetic counseling to the patients with Alagille syndrome and their families.
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http://dx.doi.org/10.1089/gte.2006.0519DOI Listing
January 2008