Publications by authors named "Yoshio Makita"

51 Publications

Case Report: A Rare Case of Esophagogastric Junctional Squamous Cell Carcinoma After the Successful Treatment of Neuroendocrine Carcinoma: Clonal Tumor Evolution Revealed by Genetic Analysis.

Front Genet 2021 15;12:608324. Epub 2021 Sep 15.

Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.

Neuroendocrine carcinoma (NEC) of the esophagogastric junction (EGJ) is a rare disease with no established treatments. Herein, we describe a case of recurrent squamous cell carcinoma (SCC) after achieving complete response to chemotherapy against NEC of the EGJ. A 67-year-old man was referred to our hospital because of epigastric discomfort. Computed tomography imaging and esophagogastroduodenoscopy revealed ulcerated tumors at the EGJ. Endoscopic biopsy revealed small tumor cells with a high nuclear/cytoplasmic ratio, suggesting small-cell NEC. Immunohistochemistry (IHC) analysis showed tumor cells with an MIB-1 index of 80%. The patient achieved complete response after 10 cycles of chemotherapy. Follow-up endoscopic examination revealed small red-colored mucosal lesions in the center of the cicatrized primary lesion. Re-biopsy detected cancer cells harboring large eosinophilic cytoplasm with keratinization and no evidence of NEC components. IHC of the cells were cytokeratin 5/6-positive and p53-negative. The tumor persisted without evidence of metastases after chemoradiotherapy, and total gastrectomy with lymph node dissection was performed. Pathological assessment of the resected specimens revealed SCC, without evidence of NEC. The patient survived without a recurrence for >3 years after the initial presentation. Somatic mutation profiles of the primary NEC and recurrent SCC were analyzed by targeted amplicon sequencing covering common cancer-related mutations. Both tumors possessed Q192X mutation, whereas S517T was found only in SCC, suggesting that both tumor components originated from a founder clone with a stop-gain mutation in . The somatic mutation profile of the tumors indicated that that loss of heterozygosity (LOH) at the gene might have occurred during the differentiation of the founder clone into NEC, while a mutation might have contributed to SCC development, indicating branching and subclonal evolution from common founder clone to both NEC and SCC. The mutation assessments provided valuable information to better understand the clonal evolution of metachronous cancers.
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http://dx.doi.org/10.3389/fgene.2021.608324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489402PMC
September 2021

Relapsing 6q24-related transient neonatal diabetes mellitus with insulin resistance: A case report.

Clin Pediatr Endocrinol 2020 3;29(4):179-182. Epub 2020 Oct 3.

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

The overexpression of imprinted genes on chromosome 6q24 causes 6q24-related transient neonatal diabetes mellitus (6q24-TNDM). Most cases of 6q24-TNDM show transient diabetes mellitus (DM) during the neonatal period, followed by relapse after puberty. These two courses of DM are both characterized by insulin insufficiency. However, there has been no previously reported case of 6q24-TNDM with insulin resistance at relapse. We report the case of a 10-yr-old Japanese girl with relapsing 6q24-TNDM. In the neonatal period, she had hyperglycemia and was treated with insulin injection until 2 mo of age. After several years of remission of DM, her HbA1c level increased to 7.4% at 10 yr of age. Homeostasis model assessment of insulin resistance (HOMA-IR) score was high at 6.2. After starting metformin therapy, her glycemic control improved along with normalization of HOMA-IR score. Using microsatellite marker analysis on the 6q24 region and array comparative genome hybridization, we diagnosed her with 6q24-TNDM due to paternally inherited duplication of 6q24. These data indicate that patients with 6q24-TNDM can develop relapsing DM with insulin resistance.
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http://dx.doi.org/10.1297/cpe.29.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534527PMC
October 2020

Severe gastrointestinal symptoms caused by a novel DDX3X variant.

Eur J Med Genet 2020 Dec 5;63(12):104058. Epub 2020 Sep 5.

Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan.

Mutations in DDX3X have recently been identified as a common cause of intellectual disability and congenital anomalies. DDX3X (Xp11.4) encodes the DEAD box RNA helicase that plays an important role in gene regulation, apoptosis, and oncogenesis. Here, we report a case of 6-year-old Japanese girl with a novel variant (NM_001193416.3: c.1574A > G; p.(Tyr525Cys), who exhibited psychomotor retardation, severe constipation, and a recurrent paralytic ileus. This is the second report of severe gastrointestinal symptoms being associated with this disease. This report expands the phenotype caused by DDX3X variants and reveals an important clinical aspect for patients and medical staff.
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http://dx.doi.org/10.1016/j.ejmg.2020.104058DOI Listing
December 2020

Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy.

Epileptic Disord 2020 Aug;22(4):501-505

Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan.

Developmental and epileptic encephalopathy is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability, in which there is additional developmental impairment independent of epileptic activity. Biallelic variants of SZT2, a known seizure threshold regulator gene, have been linked to a wide spectrum of clinical features, ranging from severe intellectual disability with refractory seizures to mild intellectual disability without seizures. Here, we describe a child with developmental and epileptic encephalopathy whose genetic testing led to the identification of novel biallelic variants of SZT2, a paternally inherited c.2798C>T, p.(Ser933Phe) variant and a maternally inherited c.4549C>T, p.(Arg1517Trp) variant. Our patient showed common clinical and radiographic features among patients with SZT2-related encephalopathy. However, neonatal-onset seizures and suppression-burst EEG activity, not previously associated with SZT2-related encephalopathy, were observed in this case. Although the seizures were controlled with carbamazepine, the developmental consequences remained profound, suggesting that the developmental impairments might be attributed to a direct effect of the SZT2 variants rather than the epileptic activity. We propose that SZT2 variants should be regarded among those that are believed to cause neonatal-onset developmental and epileptic encephalopathy with a suppression-burst pattern on EEG.
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http://dx.doi.org/10.1684/epd.2020.1187DOI Listing
August 2020

NT5E Genetic Mutation Is a Rare But Important Cause of Intermittent Claudication and Chronic Limb-Threatening Ischemia.

Circ J 2020 06 11;84(7):1183-1188. Epub 2020 Jun 11.

Department of Genome Medicine, National Center for Child Health and Development.

Background: NT5Egenetic mutations are known to result in calcification of joints and arteries (CALJA), and worldwide, 14 patients from 7 families have been reported.Methods and Results:A total of 5 patients from 2 independent families with CALJA were found in Japan. Of them, 3 complained of intermittent claudication (IC), and 1 suffered from bilateral chronic limb-threatening ischemia (CLTI). Whole-exome sequencing analysis revealed an identical mutation pattern (c.G3C on the exon 1 start codon) that was unique compared withNT5Emutations reported in other countries.

Conclusions: Vascular specialists need to recognize CALJA as a rare cause of ischemic IC and CLTI.
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http://dx.doi.org/10.1253/circj.CJ-20-0153DOI Listing
June 2020

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

Am J Hum Genet 2019 05 25;104(5):815-834. Epub 2019 Apr 25.

Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK.

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507050PMC
May 2019

Novel compound heterozygous variants in a patient with Usher syndrome type I.

Hum Genome Var 2019 28;6. Epub 2019 Jan 28.

4Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.

Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Here, we report a 12-year-old female patient with typical USH1. Targeted panel sequencing revealed compound heterozygous variants of the () gene, which confirmed the USH1 diagnosis. A novel NM_022124.5:c.130G>A/p.(Glu44Lys) was identified, expanding the mutation spectrum of .
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http://dx.doi.org/10.1038/s41439-019-0037-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348282PMC
January 2019

Genitopatellar syndrome: the first reported case in Japan.

Hum Genome Var 2018 28;5. Epub 2018 May 28.

4Education Center, Asahikawa Medical University, Asahikawa, Japan.

Genitopatellar syndrome (GPS) is mainly characterized by an absence of patellae, congenital flexion contractures of the lower limbs, psychomotor retardation, and anomalies of the external genitalia and kidneys. We report an 18-year-old female with a novel heterozygous truncating mutation in exon 17 of the gene [MC_000010.11:c.3603_3606 del, p.Arg1201fs]. This is the first report of typical GPS in a Japanese individual. The details of our findings may contribute to elucidating the mechanism underlying GPS-specific clinical features.
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http://dx.doi.org/10.1038/s41439-018-0010-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972145PMC
May 2018

Genomic Characterization of Chromosomal Insertions: Insights into the Mechanisms Underlying Chromothripsis.

Cytogenet Genome Res 2017 27;153(1):1-9. Epub 2017 Oct 27.

Division of Molecular Genetics, Institute for Comprehensive Medical Science (ICMS), and Genome and Transcriptome Analysis Center, Fujita Health University, Toyoake, Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Department of Pediatrics, Toyota Kosei Hospital, Toyota, Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, and Takeuchi Ladies Clinic/Infertility Center, Kagoshima, and Education Center, Asahikawa Medical University, Hokkaido, Japan.

Chromosomal insertions are rare structural rearrangements, and the molecular mechanisms underlying their origin are unknown. In this study, we used whole genome sequencing to analyze breakpoints and junction sequences in 4 patients with chromosomal insertions. Our analysis revealed that none of the 4 cases involved a simple insertion mediated by a 3-chromosomal breakage and rejoining events. The inserted fragments consisted of multiple pieces derived from a localized genomic region, which were shuffled and rejoined in a disorderly fashion with variable copy number alterations. The junctions were blunt ended or with short microhomologies or short microinsertions, suggesting the involvement of nonhomologous end-joining. In one case, analysis of the parental origin of the chromosomes using nucleotide variations within the insertion revealed that maternal chromosomal segments were inserted into the paternal chromosome. This patient also carried both maternal alleles, suggesting the presence of zygotic trisomy. These data indicate that chromosomal shattering may occur in association with trisomy rescue in the early postzygotic stage.
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http://dx.doi.org/10.1159/000481586DOI Listing
January 2018

SNP array screening of cryptic genomic imbalances in 450 Japanese subjects with intellectual disability and multiple congenital anomalies previously negative for large rearrangements.

J Hum Genet 2016 Apr 7;61(4):335-43. Epub 2016 Jan 7.

Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Intellectual disability (ID) is a heterogeneous condition affecting 2-3% of the population, often associated with multiple congenital anomalies (MCA). The genetic cause remains largely unexplained for most cases. To investigate the causes of ID/MCA of unknown etiology in the Japanese population, 645 subjects have been recruited for the screening of pathogenic copy-number variants (CNVs). Two screenings using bacterial artificial chromosome (BAC) arrays were previously performed, which identified pathogenic CNVs in 133 cases (20.6%; Hayashi et al., J. Hum. Genet., 2011). Here, we present the findings of the third screening using a single-nucleotide polymorphism (SNP) array, performed in 450 negative cases from our previous report. Pathogenic CNVs were found in 22 subjects (4.9%), in which 19 CNVs were located in regions where clinical significance had been previously established. Among the 22 cases, we identified PPFIA2 as a novel candidate gene for ID. Analysis of copy-neutral loss of heterozygosity (CNLOH) detected one case in which the CNLOH regions seem to be significant. The SNP array detected a modest fraction of small causative CNVs, which is explained by the fact that the majority of causative CNVs have larger sizes, and those had been mostly identified in the two previous screenings.
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http://dx.doi.org/10.1038/jhg.2015.154DOI Listing
April 2016

Detecting copy-number variations in whole-exome sequencing data using the eXome Hidden Markov Model: an 'exome-first' approach.

J Hum Genet 2015 Apr 22;60(4):175-82. Epub 2015 Jan 22.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Whole-exome sequencing (WES) is becoming a standard tool for detecting nucleotide changes, and determining whether WES data can be used for the detection of copy-number variations (CNVs) is of interest. To date, several algorithms have been developed for such analyses, although verification is needed to establish if they fit well for the appropriate purpose, depending on the characteristics of each algorithm. Here, we performed WES CNV analysis using the eXome Hidden Markov Model (XHMM). We validated its performance using 27 rare CNVs previously identified by microarray as positive controls, finding that the detection rate was 59%, or higher (89%) with three or more targets. XHMM can be effectively used, especially for the detection of >200 kb CNVs. XHMM may be useful for deletion breakpoint detection. Next, we applied XHMM to genetically unsolved patients, demonstrating successful identification of pathogenic CNVs: 1.5-1.9-Mb deletions involving NSD1 in patients with unknown overgrowth syndrome leading to the diagnosis of Sotos syndrome, and 6.4-Mb duplication involving MECP2 in affected brothers with late-onset spasm and progressive cerebral/cerebellar atrophy confirming the clinical suspect of MECP2 duplication syndrome. The possibility of an 'exome-first' approach for clinical genetic investigation may be considered to save the cost of multiple investigations.
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http://dx.doi.org/10.1038/jhg.2014.124DOI Listing
April 2015

X-linked Alport syndrome caused by splicing mutations in COL4A5.

Clin J Am Soc Nephrol 2014 Nov 2;9(11):1958-64. Epub 2014 Sep 2.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan;

Background And Objectives: X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.

Design, Setting, Participants, & Measurements: In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.

Results: Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.

Conclusions: This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.
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http://dx.doi.org/10.2215/CJN.04140414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220764PMC
November 2014

Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations.

Genet Med 2014 Dec 8;16(12):903-12. Epub 2014 May 8.

Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.

Purpose: Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined.

Methods: Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced.

Results: Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR.

Conclusion: Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects.
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http://dx.doi.org/10.1038/gim.2014.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262761PMC
December 2014

Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features.

J Hum Genet 2012 Mar 2;57(3):207-11. Epub 2012 Feb 2.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.
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http://dx.doi.org/10.1038/jhg.2012.7DOI Listing
March 2012

Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion.

J Hum Genet 2012 Mar 19;57(3):191-6. Epub 2012 Jan 19.

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

Approximately 3% of the live-born infants have major dysmorphic features, and about two-thirds of which are observed in the maxillofacial region; however, in many cases, the etiology of the dysmorphic features remains uncertain. Recently, the genome-wide screening of large patient cohorts with congenital disorders has made it possible to discover genomic aberrations corresponding to the pathogenesis. In our analyses of more than 536 cases of clinically undiagnosed multiple congenital anomalies and mental retardation (MR) by microarray-based comparative genomic hybridization, we detected two non-consanguineous unrelated patients with microdeletions at 10p11.23-p12.1, which overlapped for 957 kb, including four protein-coding genes: ARMC4, MPP7, WAC and BAMBI. As the two patients had similar phenotypes; for example, MR and multiple maxillofacial abnormalities including midface retrusion, wide mouth and large tongue, we assessed the phenotypes in detail to define the common features, using quantitative evaluations of the maxillofacial dysmorphism. The concordance of the genetic and phenotypic alterations is a good evidence of a new syndrome. Although an interstitial deletion of 10p is rare, the current study is the first trial to examine precisely the craniofacial characteristics of patients with a heterozygous deletion at 10p11.23-p12.1, and presents good evidence to diagnose potential patients with the same genetic cause.
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http://dx.doi.org/10.1038/jhg.2011.154DOI Listing
March 2012

MBTPS2 mutation causes BRESEK/BRESHECK syndrome.

Am J Med Genet A 2012 Jan 21;158A(1):97-102. Epub 2011 Nov 21.

Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.

BRESEK/BRESHECK syndrome is a multiple congenital malformation characterized by brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies, and renal anomalies or small kidneys, with or without Hirschsprung disease and cleft palate or cryptorchidism. This syndrome has only been reported in three male patients. Here, we report on the fourth male patient presenting with brain anomaly, intellectual disability, growth retardation, ectodermal dysplasia, vertebral (skeletal) anomaly, Hirschsprung disease, low-set and large ears, cryptorchidism, and small kidneys. These manifestations fulfill the clinical diagnostic criteria of BRESHECK syndrome. Since all patients with BRESEK/BRESHECK syndrome are male, and X-linked syndrome of ichthyosis follicularis with atrichia and photophobia is sometimes associated with several features of BRESEK/BRESHECK syndrome such as intellectual disability, vertebral and renal anomalies, and Hirschsprung disease, we analyzed the causal gene of ichthyosis follicularis with atrichia and photophobia syndrome, MBTPS2, in the present patient and identified an p.Arg429His mutation. This mutation has been reported to cause the most severe type of ichthyosis follicularis with atrichia and photophobia syndrome, including neonatal and infantile death. These results demonstrate that the p.Arg429His mutation in MBTPS2 causes BRESEK/BRESHECK syndrome.
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http://dx.doi.org/10.1002/ajmg.a.34373DOI Listing
January 2012

PCDH19 mutation in Japanese females with epilepsy.

Epilepsy Res 2012 Mar 1;99(1-2):28-37. Epub 2011 Nov 1.

Department of Pediatrics, School of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

Purpose: To determine the significance of PCDH19 mutations in Japanese females with epilepsy and to delineate their phenotypes.

Methods: PCDH19 sequencing analysis was performed in 116 females with various epilepsies, including 97 with Dravet syndrome (83.6%). They were referred for SCN1A analysis, and 52 carried SCN1A mutations.

Results: Seven heterozygous mutations in exon 1 were identified in 7 patients (6.0%): 2 frameshift, 2 nonsense, and 3 missense mutations. One patient was a monozygotic twin, and her sister with mild phenotype carried the same mutation. The main clinical features among these 8 patients included early seizure onset (≤25 months of age), seizure clusters (7/8), fever-associated seizures (7/8), single seizure type (6/8), and late deterioration of intellect (5/8). Seizure durations were generally up to a few minutes, and only one patient developed status epilepticus once. The main seizure types were generalized tonic-clonic (4/8), tonic (3/8) and focal seizures, with (2/8) or without secondary generalization (3/8). Myoclonic, atonic and absence seizures were extremely rare. Two patients had Dravet syndrome (25%), and this proportion was significantly smaller than that in the total subjects (p<0.01).

Conclusion: PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. Dravet syndrome was rare in our cohort.
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http://dx.doi.org/10.1016/j.eplepsyres.2011.10.014DOI Listing
March 2012

Axial spondylometaphyseal dysplasia: additional reports.

Am J Med Genet A 2011 Oct 9;155A(10):2521-8. Epub 2011 Sep 9.

Department of Pediatrics, Asahikawa Medical University, Japan.

Axial spondylometaphyseal dysplasia (SMD) (OMIM 602271) is an uncommon skeletal dysplasia characterized by metaphyseal changes of truncal-juxtatruncal bones, including the proximal femora, and retinal abnormalities. The disorder has not attracted much attention since initially reported; however, it has been included in the nosology of genetic skeletal disorders [Warman et al. (2011); Am J Med Genet Part A 155A:943-968] in part because of a recent publication of two additional cases [Isidor et al. (2010); Am J Med Genet Part A 152A:1550-1554]. We report here on the clinical and radiological manifestations in seven affected individuals from five families (three sporadic cases and two familial cases). Based on our observations and Isidor's report, the clinical and radiological hallmarks of axial SMD can be defined: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and function rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram. The radiological hallmarks include short ribs with flared, cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. Equally affected sibling pairs of opposite gender and parental consanguinity are strongly suggestive of autosomal recessive inheritance.
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http://dx.doi.org/10.1002/ajmg.a.34192DOI Listing
October 2011

Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation.

J Hum Genet 2011 Aug 14;56(8):609-12. Epub 2011 Jul 14.

Department of Pediatrics, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka, Japan.

Autosomal dominant nocturnal frontal lobe epilepsy is a familial partial epilepsy syndrome and the first human idiopathic epilepsy known to be related to specific gene defects. Clinically available molecular genetic testing reveals mutations in three genes, CHRNA4, CHRNB2 and CHRNA2. Mutations in CHRNA4 have been found in families from different countries; the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. Clear evidence for founder effect was not reported among them, including a haplotype study carried out on the Australian and Norwegian families. Japanese and Koreans, because of their geographical closeness and historical interactions, show greater genetic similarities than do the populations of other countries where the mutation is found. Haplotype analysis in the two previously reported families showed, however, independent occurrence of the Ser284Leu mutation. The affected nucleotide was highly conserved and associated with a CpG hypermutable site, while other CHRNA4 mutations were not in mutation hot spots. Association with a CpG site accounts for independent occurrence of the Ser284Leu mutation.
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http://dx.doi.org/10.1038/jhg.2011.69DOI Listing
August 2011

Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH).

Hum Genet 2012 Jan 7;131(1):99-110. Epub 2011 Jul 7.

Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

The CASK gene encoding a member of the membrane-associated guanylate kinase protein family is highly expressed in the mammalian nervous system of both adults and fetuses, playing several roles in neural development and synaptic function. Recently, CASK aberrations caused by both mutations and deletions have been reported to cause severe mental retardation (MR), microcephaly and disproportionate pontine and cerebellar hypoplasia (MICPCH) in females. Here, mutations and copy numbers of CASK were examined in ten females with MR and MICPCH, and the following changes were detected: nonsense mutations in three cases, a 2-bp deletion in one case, mutations at exon-intron junctions in two cases, heterozygous deletions encompassing CASK in two cases and interstitial duplications in two cases. Except for the heterozygous deletions, each change including the intragenic duplications potentially caused an aberrant transcript, resulting in CASK null mutations. The results provide novel mutations and copy number aberrations of CASK, causing MR with MICPCH, and also demonstrate the similarity of the phenotypes of MR with MICPCH regardless of the CASK mutation.
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http://dx.doi.org/10.1007/s00439-011-1047-0DOI Listing
January 2012

5.78 Mb terminal deletion of chromosome 15q in a girl, evaluation of NR2F2 as candidate gene for congenital heart defects.

Eur J Med Genet 2011 May-Jun;54(3):354-6. Epub 2010 Dec 21.

Department of Pediatrics, Asahikawa Medical College, 2-1-1-1 Midorigaoka Higashi, Asahikawa, Hokkaido 078-8510, Japan.

All patients with terminal deletion of chromosome 15q have been reported to show intrauterine growth retardation, postnatal growth retardation, abnormal facial appearance and developmental delay. Haploinsufficiency of IGF1R was considered to be responsible for these symptoms. However, it is difficult to explain other symptoms seen in some of the patients, such as congenital heart defects by the absence of IGF1R alone. Here, we reported a patient with congenital heart defects and a 5.78 Mb terminal deletion of chromosome 15q detected by array-CGH. Among the patients reported to share congenital heart defects and terminal deletion of chromosome 15q, our patient had the smallest deletion. Evaluating the deletion map, NR2F2 was considered a candidate gene contributing to congenital heart defects in patients with terminal deletion of chromosome 15q.
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http://dx.doi.org/10.1016/j.ejmg.2010.12.004DOI Listing
September 2011

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

Association of SLC6A9 gene variants with human essential hypertension.

J Atheroscler Thromb 2009 Jun 25;16(3):201-6. Epub 2009 Jun 25.

Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Itabashi 173-8610, Tokyo, Japan.

Aim: We previously identified a quantitative trait locus (QTL) on rat chromosome 5 that appeared to be primarily controlled by the sympathetic nervous system. Because sympathetic overactivity is related to hypertension, solute carrier family 6, member 9 (SLC6A9) is a candidate gene for the connection of this QTL with blood pressure regulation. In the present study, we therefore explored the role of SLC6A9 genetic variations in human essential hypertension (EH).

Methods: We evaluated three single nucleotide polymorphisms (SNPs) (rs2286245, rs3791124 and rs2486001) in 758 essential hypertension patients and 726 controls. Polymorphism-related genotypes were determined with TaqMan assays.

Results: The allelic frequency of rs2286245 (C versus T, p=0.032) showed significant differences between EH and normotensive controls (NT) groups. The genotypic distribution of rs3791124 in its dominant model (AA+GA versus GG, p=0.027) also showed significant differences between EH and NT groups. The genotype and allele distributions of rs2486001 did not exhibit any significant differences.

Conclusion: We found an association between SLC6A9 gene polymorphisms and essential hypertension in a Japanese population, suggesting that SLC6A9 is a susceptibility locus for essential hypertension.
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http://dx.doi.org/10.5551/jat.e125DOI Listing
June 2009

Paternal allele of IGF2 gene haplotype CTG is associated with fetal and placental growth in Japanese.

Pediatr Res 2009 Aug;66(2):135-9

Department of Pediatrics, Asahikawa Medical College, Asahikawa, Hokkaido 078-8510, Japan.

IGF-II associates with feto-placental growth in rodent and human. We determined three tag-single nucleotide polymorphisms (SNPs) to investigate haplotype frequency of IGF2 relative to size at birth in 134 healthy Japanese infants. In addition, a total of 276 healthy infants were investigated to determine whether common genetic variation of IGF2 might contribute to feto-placental growth using haplotype analysis. Further, quantitative methylation analysis of the IGF2/H19 was performed using the MassARRAY Compact system. In the initial study, the frequency of haplotype CTG from the paternal allele in small for date (SFD) infants was significantly higher than that in non-SFD infants (p = 0.03). In a second study, the CTG haplotype infants exhibited significantly lower birth length, weight, and placental weight compared with non-CTG infants. Further, the number of infants less than -1.5 SD (SD) birth weight in CTG haplotype was higher than those in non-CTG infants. There was no significant difference in the methylation status of H19/IGF2 in the two haplotypes. In conclusion, inheriting the IGF2 CTG haplotype from a paternal allele results in reduced feto-placental growth, but it is not associated with the methylation status of IGF2/H19.
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http://dx.doi.org/10.1203/PDR.0b013e3181a9e818DOI Listing
August 2009

Heterozygous deletion at 14q22.1-q22.3 including the BMP4 gene in a patient with psychomotor retardation, congenital corneal opacity and feet polysyndactyly.

Am J Med Genet A 2008 Nov;146A(22):2905-10

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

Here we report on a 1-year-old Japanese girl with psychomotor retardation, bilateral congenital corneal opacity and bilateral postaxial polysyndactyly of the feet. Although she had a normal female karyotype, our in-house bacterial artificial chromosome (BAC)-based array-CGH analysis successfully detected at least a 2.7-Mb heterozygous deletion at 14q22.1-q22.3 harboring 18 protein-coding genes. Among the genes, BMP4 was a candidate for the gene causing the abnormalities of both the eye and digits. It was previously reported that the BMP family was correlated with the morphogenesis of digits and ocular development, and Bmp4 heterozygous null mice revealed skeletal abnormalities including polydactyly and ocular anterior segment abnormalities. Patients with a deletion including BMP4 also hadabnormalities of the eye and digits. These previous reports support that a haplo-insufficiency of the BMP4 gene likely caused the congenital ocular and digit abnormalities. Moreover, among the other genes contained in the deletion, GMFB is a candidate for the gene responsible for the psychomotor retardation.
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http://dx.doi.org/10.1002/ajmg.a.32519DOI Listing
November 2008

Acute disseminated encephalomyelitis in an infant with incontinentia pigmenti.

Brain Dev 2009 Sep 21;31(8):625-8. Epub 2008 Sep 21.

Department of Pediatrics, Abashiri Kosei Hospital, Abashiri, Hokkaido, Japan.

We report the case of a female Japanese infant who was diagnosed with incontinentia pigmenti (IP) on the basis of the clinical and pathological findings of characteristic skin lesions and the detection of deletion in the nuclear factor-kappa B essential modulator gene at Xq28. The patient developed repetitive seizures at the age of 7 months when she was diagnosed with acute disseminated encephalomyelitis (ADEM), an inflammatory demyelinating disease of the central nervous system that often occurs after vaccination or infection. The causative infectious agent in this patient seemed to be Mycoplasma pneumoniae because of the increased titer of its serum antibody and the detection of its DNA in the initial cerebrospinal fluid sample. This patient showed significant improvement on receiving immunosuppressive therapy with corticosteroids. This is the second case report presenting an IP patient susceptible to ADEM, and therefore, ADEM should be considered early in the differential diagnosis of acute neurological illness for IP patients.
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http://dx.doi.org/10.1016/j.braindev.2008.08.010DOI Listing
September 2009

A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions.

Brain Dev 2009 Jan 21;31(1):27-33. Epub 2008 Jul 21.

Department of Pediatrics, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

Background: The underlying genetic abnormalities of rare familial idiopathic epilepsy have been identified, such as mutation in KCNQ2, a K(+) channel gene. Yet, few genetic abnormalities have been reported for commoner epilepsy, i.e., sporadic idiopathic epilepsy, which share a phenotype similar to those of familial epilepsy.

Objective: To search for the genetic cause of seizures in a girl with the diagnosis of non-familial benign neonatal convulsions, and define the consequence of the genetic abnormality identified.

Methods: Genetic abnormality was explored within candidate genes for benign familial neonatal and infantile convulsions, such as KCNQ2, 3, 5, KCNE2, SCN1A and SCN2A. The electrophysiological properties of the channels harboring the identified mutation were examined. Western blotting and immunostaining were employed to characterize the expression and intracellular localization of the mutant channel molecules.

Results: A novel heterozygous mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified in the patient. The mutation was de novo verified by parentage analysis. The mutation was associated with impaired functions of KCNQ K(+) channel. The mutant channels were expressed on the cell surface.

Conclusion: The mutant Phe304del of KCNQ2 leads to null function of the KCNQ K(+) channel but the mutation does not alter proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy.
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http://dx.doi.org/10.1016/j.braindev.2008.05.010DOI Listing
January 2009

The CASK gene harbored in a deletion detected by array-CGH as a potential candidate for a gene causative of X-linked dominant mental retardation.

Am J Med Genet A 2008 Aug;146A(16):2145-51

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

Here we report on a 5-year-old Japanese girl with developmental delay and microcephaly. Although she had a normal karyotype, a bacterial artificial chromosome-based array-comparative genome hybridization analysis detected a de novo 4.0-Mb heterozygous deletion at Xp11.3-p11.4 harboring nine genes. By comparison with a healthy carrier mother of a boy with atypical Norrie disease having a smaller deletion in the same region, we excluded four genes as candidates whose haploinsufficiency would be causative for developmental delay. Among the other five genes, CASK seems to be the most likely candidate for a causative gene, because it is strongly expressed in fetal brain and plays important roles in neural development and synaptic function. We confirmed that the expression of CASK mRNA was decreased in the patient compared with healthy controls and the patient's X-chromosomal inactivation was not skewed. These results suggested that the genetic deletion of CASK results in haploinsufficiency, which might be causative for the patient's developmental delay or mental retardation. (c) 2008 Wiley-Liss, Inc.
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http://dx.doi.org/10.1002/ajmg.a.32433DOI Listing
August 2008

Association between fatty acid binding protein 3 gene variants and essential hypertension in humans.

Am J Hypertens 2008 Jun 10;21(6):691-5. Epub 2008 Apr 10.

Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

Background: We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans.

Methods: We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data.

Results: The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences.

Conclusion: We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.
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http://dx.doi.org/10.1038/ajh.2008.40DOI Listing
June 2008

Association of TNFRSF4 gene polymorphisms with essential hypertension.

J Hypertens 2008 May;26(5):902-13

Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Essential hypertension is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. The TNFRSF4 (tumor necrosis factor receptor superfamily, member 4) gene was one of the genes that showed altered renal expression in long-term salt loading in mice. Moreover, association of the TNFRSF4 and TNFSF4 (tumor necrosis factor (ligand) superfamily, member 4) genes with myocardial infarction was recently reported. Since essential hypertension is a well-known risk factor for myocardial infarction, we hypothesized that TNFRSF4 could be a susceptibility gene for essential hypertension.

Methods: We performed a case-control study of TNFRSF4 in two independent population.

Results: Extensive investigation of single nucleotide polymorphisms of the entire gene suggested that it resided in one linkage disequilibrium block, and four single nucleotide polymorphisms in the 5' flanking region sufficiently represented major haplotypes. In the combined population, the frequency of the most frequent haplotype, C-C-A-A, was significantly lower (P = 8.07 x 10(-5)) and that of the second most frequent haplotype, C-T-G-A, was significantly higher (P = 6.07 x 10(-4)) in hypertensive subjects than in control subjects. This difference was observed only in female patients. The C-T-G-A haplotype showed a lower promoter activity than other haplotypes, suggesting a relationship with disease susceptibility.

Conclusion: Our results suggest that TNFRSF4 is a female-specific susceptible gene for essential hypertension.
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http://dx.doi.org/10.1097/HJH.0b013e3282f6a65eDOI Listing
May 2008
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