隐睾及隐睾合并其他泌尿生殖系统畸形的外显子测序分析

目的对隐睾及隐睾合并其他泌尿生殖系统畸形的不同表型患儿进行外显子测序,以探索不同临床表型的分子病因。方法提取19例隐睾及隐睾合并其他泌尿生殖系统畸形患儿外周血基因组DNA进行外显子测序,并对测序结果进行生物信息学分析,其中3例行全基因外显子测序,16例行常见基因外显子测序,再采用Sanger测序对获得候选致病突变的患儿及其父母的外周血样本进行突变位点验证。结果本研究纳入的19例患儿中,6例外显子测序结果经生物信息学分析后发现存在异常结果,并提示有3个基因可能与相关表型发病有关:①AR基因发生3处错义突变(c.1600C>A;p.Pro534Thr)、(c.2599G>A;p.Val867Met)和(c.528C>A;p.Ser176Arg);②NR5A1基因发生移码突变(c.442delG;p.Glu148Serfs*148)和错义突变(c.43G>A;p.Val15Met);③ATRX基因发生剪切位点突变(c.4317+13T>C)。其中c.2599G>A和c.43G>A为已知突变,其余4处未见相关研究报道,为新发突变。Sanger测序结果表明6处突变均得以验证,5例患儿母亲存在对应位点突变、患儿父亲未见异常,1例患儿父母均未见异常。结论AR基因错义突变、NR5A1移码和错义突变及ATRX的剪切位点突变可能是隐睾及隐睾合并其他泌尿生殖系统畸形发病的危险因素。

Exon sequencing of cryptorchidism and other associated urogenital malformations

Objective To perform exon sequencing in children with cryptorchidism and other associated urogenital malformations for elucidating the molecular etiologies of different clinical phenotypes.Methods Exome sequencing was performed for nineteen samples.Potential candidate variants were confirmed by Sanger sequencing and then validated in their parents.Results Among 6 mutations,there were 3 mutations in AR gene,2 mutations in NR5A1 gene and 1 mutation in ATRX gene.There were 6 each of missense mutations:(c.1600C>A;p.Pro534Thr),(c.2599G>A;p.Val867Met)and(c.528C>A;p.Ser176Arg)in AR gene;frameshift mutation(c.442delG;p.Glu148Serfs*148);missense mutation(c.43G>A;p.Val15Met)in NR5A1 gene;splice site mutation(c.4317+13T>C)in ATRX gene.Conclusion AR,NR5A1 and ATRX variants are probable risk factors for cryptorchidism and other urinary malformations of susceptible candidates.