尿道下裂
遗传学
突变
生物
基因组
拷贝数变化
计算生物学
医学
基因
作者
Masafumi Kon,Erina Suzuki,Vũ Chí Dũng,Yukihiro Hasegawa,Takahiko Mitsui,Koji Muroya,Katsuhiko Ueoka,Noboru Igarashi,Keisuke Nagasaki,Yuji Oto,Takashi Hamajima,Keiko Yoshino,Maki Igarashi,Yuko Kato-Fukui,Kazuhiko Nakabayashi,Keiko Hayashi,Kenichiro Hata,Yoichi Matsubara,Kyoji Moriya,Tsutomu Ogata,Katsuya Nonomura,Maki Fukami
出处
期刊:Human Reproduction
[Oxford University Press]
日期:2015-01-20
卷期号:30 (3): 499-506
被引量:35
标识
DOI:10.1093/humrep/deu364
摘要
What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) in the genome?Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation.Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias.Systematic mutation screening and genome-wide copy-number analysis of 62 patients.The study group consisted of 57 Japanese and five Vietnamese patients with non-syndromic hypospadias. Systematic mutation screening was performed for 25 known causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide alterations were assessed by in silico assays. The frequencies of polymorphisms in the patient group were compared with those in the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized by fluorescence in situ hybridization.Seven of 62 patients with anterior or posterior hypospadias carried putative pathogenic mutations, such as hemizygous mutations in AR, a heterozygous mutation in BNC2, and homozygous mutations in SRD5A2 and HSD3B2. Two of the seven patients had mutations in multiple genes. We did not find any rare polymorphisms that were abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome.The patient group consisted solely of Japanese and Vietnamese individuals and clinical and hormonal information of the patients remained rather fragmentary. In addition, mutation analysis focused on protein-altering substitutions.Our data provide evidence that pathogenic mutations can underlie both mild and severe hypospadias and that HSD3B2 mutations cause non-syndromic hypospadias as a sole clinical manifestation. Most importantly, this is the first report documenting possible oligogenicity of non-syndromic hypospadias.This study was funded by the Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology; by the Grant-in-Aid from the Japan Society for the Promotion of Science; by the Grants from the Ministry of Health, Labour and Welfare, from the National Center for Child Health and Development and from the Takeda Foundation. The authors have no competing interests to disclose.Not applicable.
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