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目的探讨46,XY外生殖器畸形的临床及分子遗传学特征,并分析二者相关性。方法 2004年1月至2014年12月因外生殖器畸形就诊于上海交通大学医学院附属瑞金医院儿内科的染色体为46,XY的患儿77例,收集患儿的临床资料,分析总结其临床特征及实验室检查特点,采用候选基因分析策略,选择15个候选基因,利用依托Illumina-Miseq测序平台的二代测序(next generation sequencing,NGS)技术对候选基因的全外显子测序筛查突变。结果 77例46,XY外生殖器畸形患儿临床表型多样。NGS检测到18例患儿存在候选基因有氨基酸改变的突变位点或多态性位点,其中9例患儿存在6种5α-还原酶2型(steroid-5-alpha-reductase,alpha polypeptide 2 gene,SRD5A2)基因变异,包括一处以往未见报道突变位点。在4例患儿中检测到4种雄激素受体(androgen receptor,AR)基因的变异,包含1处新发现突变。2例患儿检测到MAMLD1基因的1处纯合多态性位点。1例患儿中存在INSL3基因的复合杂合改变。1例患儿检测到MID1基因纯合突变。另有1例患儿检测NR5A1基因多态性纯合改变。结论 46,XY外生殖器畸形临床表现多样,以严重型尿道下裂为主。外生殖器发育过程中相关基因的突变在尿道下裂患儿中的检出率较高(14/64,21.8%)。这其中以SRD5A2和AR的突变为最常见,MAMLD1、INSL3、MID1和NR5A1作为尿道下裂的候选基因,尽管阳性检出率不高,但是亦不可忽视。
Objective To investigate the clinical and molecular genetic characteristics of 46 and XY external genital malformations and to analyze their correlation. Methods From January 2004 to December 2014, 77 patients with chromosome 46 and XY were admitted to Ruijin Hospital of Shanghai Jiaotong University School of Medicine for external genital malformation. The clinical data of children were collected and the clinical features were analyzed And laboratory tests, 15 candidate genes were selected using candidate gene analysis strategy, and all-exon sequencing of candidate genes was screened by next generation sequencing (NGS) based on Illumina-Miseq sequencing platform. Results 77 cases 46, XY genital malformations in children with various clinical phenotypes. NGS detected 18 cases of children with candidate amino acid mutations or polymorphic sites, of which 9 cases of children there are 6 kinds of 5α-reductase type 2 (steroid-5-alpha polypeptide 2, alpha polypeptide 2 gene, SRD5A2) gene mutations, including a previously not reported mutation sites. Four kinds of androgen receptor (AR) gene mutations were detected in four children, including one newly found mutation. Two cases of MAMLD1 gene detected a homozygous loci. One case of children with INSL3 gene complex heterozygous changes. One patient had a homozygous mutation of MID1. Another case of children detected NR5A1 gene polymorphism homozygous changes. Conclusion 46, XY genital malformations varied clinical manifestations, mainly to severe hypospadias. The mutations of related genes in the development of external genitalia were higher in children with hypospadias (14 / 64,21.8%). Among them, the mutations of SRD5A2 and AR are the most common, and MAMLD1, INSL3, MID1 and NR5A1 are the candidate genes of hypospadias. Although the positive detection rate is not high, it can not be neglected.