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1.
Hum Genome Var ; 9(1): 9, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361766

RESUMO

We describe the case of a male patient with orofaciodigital (OFD) syndrome type XVI with a homozygous variant of TMEM107 (p.Phe106del) and the additional findings of tibial dysplasia, which is a pivotal finding of OFD syndrome type IV. His family history included two fetuses with anencephaly with or without cleft lip/palate and polydactyly with no genetic information. Careful attention should be given to the interpretation of this rare pattern.

2.
Eur J Med Genet ; 63(11): 104057, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32877735

RESUMO

Here, we present the case of a 15-year-old Japanese girl with Dystonia 28, childhood-onset; DYT28 (MIM#606834) showing early-onset generalized progressive dystonia and status dystonicus. The patient was genetically undiagnosed and had not responded to various medications. By trio-based whole exome sequencing and in silico analyses, we identified a de novo heterozygous variant of KMT2B: NM_014727.2: c.7828C > T, p(Arg2610Cys). Globus pallidus internus deep brain stimulation (GPi-DBS) therapy was considered; however, the therapy could not be performed due to the patient's poor nutritional status and repeated infections. GPi-DBS is considered to be an effective treatment for patients with KMT2B mutations, and genetic diagnosis is important before progression to status dystonicus.


Assuntos
Distonia/genética , Histona-Lisina N-Metiltransferase/genética , Criança , Distonia/patologia , Feminino , Humanos , Mutação de Sentido Incorreto , Fenótipo
3.
Hum Genome Var ; 7: 11, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32337051

RESUMO

Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in mitochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the SLC25A20 gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.

4.
Hum Genome Var ; 6: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31098032

RESUMO

Cornelia de Lange syndrome (CdLS) is a cohesinopathy caused by genetic variations. We present a female with SMC1A-associated CdLS with a novel SMC1A truncation mutation (p. Arg499Ter), transposition of the great arteries, and periodic intractable seizures from 40 months of age. A review of the literature revealed that a seizure-free period after birth of at least 15 months is required for these patients to be able to walk, irrespective of the epileptic course.

5.
Clin Case Rep ; 6(2): 330-336, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29445472

RESUMO

A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge, mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in ASXL3 gene in addition to typical findings of BRPS.

6.
J Hum Genet ; 60(1): 27-34, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25391606

RESUMO

In this study, we describe three unrelated Japanese patients with hearing loss and symphalangism who were diagnosed with proximal symphalangism (SYM1), atypical multiple synostosis syndrome (atypical SYNS1) and stapes ankylosis with broad thumb and toes (SABTT), respectively, based on the clinical features. Surgical findings in the middle ear were similar among the patients. By next-generation and Sanger sequencing analyses, we identified two novel mutations, c.559C>G (p.P178A) and c.682T>A (p.C228S), in the SYM1 and atypical SYNS1 families, respectively. No pathogenic changes were found in the protein-coding regions, exon-intron boundaries or promoter regions of the NOG, GDF5 or FGF9 genes in the SABTT family. Such negative molecular data suggest there may be further genetic heterogeneity underlying SYNS1, with the involvement of at least one additional gene. Stapedotomy resulted in good hearing in all patients over the long term, indicating no correlation between genotype and surgical outcome. Given the overlap of the clinical features of these syndromes in our patients and the molecular findings, the diagnostic term 'NOG-related-symphalangism spectrum disorder (NOG-SSD)' is advocated and an unidentified gene may be responsible for this disorder.


Assuntos
Anquilose/genética , Ossos do Carpo/anormalidades , Proteínas de Transporte/genética , Anormalidades Congênitas/genética , Deformidades Congênitas do Pé/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/genética , Mutação , Estribo/anormalidades , Sinostose/genética , Ossos do Tarso/anormalidades , Adulto , Feminino , Fator 9 de Crescimento de Fibroblastos/genética , Fator 5 de Diferenciação de Crescimento/genética , Perda Auditiva/genética , Humanos , Japão , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
7.
Cell Signal ; 26(11): 2446-59, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25064455

RESUMO

Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants. Our results indicated diminished enzyme activity in the two mutants we analyzed (Gly673Asp and Ile678Thr; based on PDE4D4 residue numbering). Ectopic expression of PDE4D mutants in HEK293 cells demonstrated this reduction in activity, which was identified by increased cAMP levels. However, the cells from an acrodysostosis patient showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Protein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing mutant isoforms with a lowered PDE4D activity. Skeletal radiographs of 10-week-old knockout (KO) rats showed that the distal part of the forelimb was shorter than in wild-type (WT) rats and that all the metacarpals and phalanges were also shorter in KO, as the name acrodysostosis implies. Like the G-protein α-stimulatory subunit and PRKAR1A, PDE4D critically regulates the cAMP signal transduction pathway and influences bone formation in a way that activity-compromising PDE4D mutations can result in skeletal dysplasia. We propose that specific inhibitory PDE4D mutations can lead to the molecular pathology of acrodysostosis without hormone resistance but that the pathological phenotype may well be dependent on an over-compensatory induction of other PDE4 isoforms that can be expected to be targeted to different signaling complexes and exert distinct effects on compartmentalized cAMP signaling.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Disostoses , Heterozigoto , Deficiência Intelectual , Simulação de Acoplamento Molecular , Mutação de Sentido Incorreto , Osteocondrodisplasias , Sistemas do Segundo Mensageiro/genética , Adolescente , Adulto , Substituição de Aminoácidos , Animais , Criança , Pré-Escolar , Proteínas Quinases Dependentes de AMP Cíclico/química , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Disostoses/diagnóstico por imagem , Disostoses/enzimologia , Disostoses/genética , Feminino , Células HEK293 , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Radiografia , Ratos , Ratos Mutantes
9.
J Obstet Gynaecol Res ; 39(11): 1545-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23815237

RESUMO

Lenz microphthalmia syndrome comprises microphthalmia-anophthalmia with mental retardation, malformed ears and skeletal anomalies, and is inherited in an X-linked recessive pattern. In 2004, it was reported that the missense mutation (BCL-6 co-repressor gene [BCOR] c.254C>T, p.P85L) in a single family with Lenz microphthalmia syndrome co-segregated with the disease phenotype. We report a case of prenatal diagnosis for X-linked recessive Lenz microphthalmia syndrome with the mutation. A 32-year-old gravida 5, para 2 Japanese woman was referred to Nagoya City University Hospital at 15 weeks of gestation. After genetic counseling and informed consent, amniocentesis was performed for fetal karyotyping, which was 46,XY. Using the extracted DNA from cultured amniotic cells, fetal search for BCOR c.254C>T mutation was undertaken. The couple requested medical termination of pregnancy, and the postabortion examination confirmed the diagnosis. This is the third report of a BCOR mutation, associated with X-linked syndromic microphthalmia, and most importantly, it is always the same mutation. The prenatal genetic diagnosis of the Lenz microphthalmia syndrome allowed time for parental counseling and delivery planning.


Assuntos
Anoftalmia/diagnóstico , Microftalmia/diagnóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Adulto , Anoftalmia/genética , Cromossomos Humanos X , Feminino , Humanos , Microftalmia/genética , Gravidez , Diagnóstico Pré-Natal
10.
Am J Med Genet A ; 161A(6): 1221-37, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23637025

RESUMO

Mutations in the components of the SWItch/sucrose nonfermentable (SWI/SNF)-like chromatin remodeling complex have recently been reported to cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and ARID1B-related intellectual disability (ID) syndrome. We detail here the genotype-phenotype correlations for 85 previously published and one additional patient with mutations in the SWI/SNF complex: four with SMARCB1 mutations, seven with SMARCA4 mutations, 37 with SMARCA2 mutations, one with an SMARCE1 mutation, three with ARID1A mutations, and 33 with ARID1B mutations. The mutations were associated with syndromic ID and speech impairment (severe/profound in SMARCB1, SMARCE1, and ARID1A mutations; variable in SMARCA4, SMARCA2, and ARID1B mutations), which was frequently accompanied by agenesis or hypoplasia of the corpus callosum. SMARCB1 mutations caused "classical" CSS with typical facial "coarseness" and significant digital/nail hypoplasia. SMARCA4 mutations caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. SMARCA2 mutations caused NCBRS, typically with short stature, sparse hair, a thin vermillion of the upper lip, an everted lower lip and prominent finger joints. A SMARCE1 mutation caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. ARID1A mutations caused the most severe CSS with severe physical complications. ARID1B mutations caused CSS without typical facial coarseness and with mild digital/nail hypoplasia, or caused syndromic ID. Because of the common underlying mechanism and overlapping clinical features, we propose that these conditions be referred to collectively as "SWI/SNF-related ID syndromes".


Assuntos
Anormalidades Múltiplas/genética , Montagem e Desmontagem da Cromatina/genética , Face/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Hipotricose/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fatores de Transcrição/genética , Proteínas Cromossômicas não Histona/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Fácies , Feminino , Estudos de Associação Genética , Humanos , Masculino , Mutação , Proteínas Nucleares/genética , Proteína SMARCB1 , Síndrome
11.
BMC Med Genet ; 14: 56, 2013 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-23705809

RESUMO

BACKGROUND: Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands. METHODS: We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient's clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon-intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2(-ΔΔCT)) method were used to determine the pathogenicity associated with gene substitutions. RESULTS: SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A. CONCLUSIONS: The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA.


Assuntos
Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Adolescente , Adulto , Alelos , Povo Asiático/genética , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Éxons , Feminino , Genética Populacional/métodos , Bócio Nodular/etnologia , Perda Auditiva Neurossensorial/etnologia , Heterozigoto , Homozigoto , Humanos , Lactente , Ilhas/epidemiologia , Japão/epidemiologia , Masculino , Taxa de Mutação , Linhagem , Fenótipo , Splicing de RNA , Radiografia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transportadores de Sulfato , Osso Temporal/diagnóstico por imagem , Aqueduto Vestibular/anormalidades , Adulto Jovem
13.
J Hum Genet ; 57(12): 787-95, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23135232

RESUMO

The Japanese Archipelago stretches over 4000 km from north to south, and is the homeland of the three human populations; the Ainu, the Mainland Japanese and the Ryukyuan. The archeological evidence of human residence on this Archipelago goes back to >30 000 years, and various migration routes and root populations have been proposed. Here, we determined close to one million single-nucleotide polymorphisms (SNPs) for the Ainu and the Ryukyuan, and compared these with existing data sets. This is the first report of these genome-wide SNP data. Major findings are: (1) Recent admixture with the Mainland Japanese was observed for more than one third of the Ainu individuals from principal component analysis and frappe analyses; (2) The Ainu population seems to have experienced admixture with another population, and a combination of two types of admixtures is the unique characteristics of this population; (3) The Ainu and the Ryukyuan are tightly clustered with 100% bootstrap probability followed by the Mainland Japanese in the phylogenetic trees of East Eurasian populations. These results clearly support the dual structure model on the Japanese Archipelago populations, though the origins of the Jomon and the Yayoi people still remain to be solved.


Assuntos
Povo Asiático/genética , Genética Populacional/história , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Cromossomos Humanos/genética , DNA Mitocondrial/genética , Ecossistema , História Antiga , Humanos , Filogenia
14.
Autism Res Treat ; 2012: 724072, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22934180

RESUMO

Mutations in the X-linked genes neuroligin 3 (NLGN3) and neuroligin 4X (NLGN4X) were first implicated in the pathogenesis of X-linked autism in Swedish families. However, reports of mutations in these genes in autism spectrum disorder (ASD) patients from various ethnic backgrounds present conflicting results regarding the etiology of ASD, possibly because of genetic heterogeneity and/or differences in their ethnic background. Additional mutation screening study on another ethnic background could help to clarify the relevance of the genes to ASD. We scanned the entire coding regions of NLGN3 and NLGN4X in 62 Japanese patients with ASD by polymerase chain reaction-high-resolution melting curve and direct sequencing analyses. Four synonymous substitutions, one in NLGN3 and three in NLGN4X, were identified in four of the 62 patients. These substitutions were not present in 278 control X-chromosomes from unrelated Japanese individuals and were not registered in the database of Single Nucleotide Polymorphisms build 132 or in the Japanese Single Nucleotide Polymorphisms database, indicating that they were novel and specific to ASD. Though further analysis is necessary to determine the physiological and clinical importance of such substitutions, the possibility of the relevance of both synonymous and nonsynonymous substitutions with the etiology of ASD should be considered.

15.
Nat Genet ; 44(4): 376-8, 2012 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-22426308

RESUMO

By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B.


Assuntos
Anormalidades Múltiplas/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Células Cultivadas , Proteínas Cromossômicas não Histona/genética , Variações do Número de Cópias de DNA/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Exoma , Face/anormalidades , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Pescoço/anormalidades , Proteínas Nucleares/genética , Proteína SMARCB1 , Análise de Sequência de DNA , Fatores de Transcrição/genética
16.
J Hum Genet ; 57(3): 207-11, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22301465

RESUMO

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.


Assuntos
Mutação de Sentido Incorreto , Fatores de Transcrição NFI/genética , Síndrome de Sotos/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Fácies , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Multimerização Proteica/genética , Alinhamento de Sequência , Adulto Jovem
17.
Am J Med Genet A ; 155A(7): 1511-6, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21671394

RESUMO

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Doenças Hematológicas/genética , Mutação/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Alelos , Face/anormalidades , Ordem dos Genes , Testes Genéticos , Genótipo , Doenças Hematológicas/diagnóstico , Humanos , Fenótipo , Prognóstico , Doenças Vestibulares/diagnóstico
18.
Science ; 326(5959): 1541-5, 2009 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-20007900

RESUMO

Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations.


Assuntos
Povo Asiático/genética , Emigração e Imigração , Etnicidade/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Algoritmos , Ásia , Povo Asiático/história , Teorema de Bayes , Análise por Conglomerados , Emigração e Imigração/história , Etnicidade/história , Fluxo Gênico , Genótipo , Geografia , História Antiga , Humanos , Idioma , Linguística , Análise de Sequência com Séries de Oligonucleotídeos , Filogenia , Análise de Componente Principal
19.
J Hum Genet ; 54(5): 304-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19343044

RESUMO

The Kabuki syndrome (KS, OMIM 147920), also known as the Niikawa-Kuroki syndrome, is a multiple congenital anomaly/mental retardation syndrome characterized by a distinct facial appearance. The cause of KS has been unidentified, even by whole-genome scan with array comparative genomic hybridization (CGH). In recent years, high-resolution oligonucleotide array technologies have enabled us to detect fine copy number alterations. In 17 patients with KS, molecular karyotyping was carried out with GeneChip 250K NspI array (Affymetrix) and Copy Number Analyser for GeneChip (CNAG). It showed seven copy number alterations, three deleted regions and four duplicated regions among the patients, with the exception of registered copy number variants (CNVs). Among the seven loci, only the region of 9q21.11-q21.12 (approximately 1.27 Mb) involved coding genes, namely, transient receptor potential cation channel, subfamily M, member 3 (TRPM3), Kruppel-like factor 9 (KLF9), structural maintenance of chromosomes protein 5 (SMC5) and MAM domain containing 2 (MAMDC2). Mutation screening for the genes detected 10 base substitutions consisting of seven single-nucleotide polymorphisms (SNPs) and three silent mutations in 41 patients with KS. Our study could not show the causative genes for KS, but the locus of 9q21.11-q21.12, in association with a cleft palate, may contribute to the manifestation of KS in the patient. As various platforms on oligonucleotide arrays have been developed, higher resolution platforms will need to be applied to search tiny genomic rearrangements in patients with KS.


Assuntos
Anormalidades Múltiplas/genética , Análise Mutacional de DNA , Aberrações Cromossômicas , Cromossomos Humanos/genética , Biologia Computacional , Feminino , Dosagem de Genes/genética , Humanos , Cariotipagem , Masculino , Reprodutibilidade dos Testes , Deleção de Sequência , Síndrome
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