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 associations of single nucleotide polymorphisms(SNP) of human growth hormone receptor(GHR) with genetic susceptibility to idiopathic short stature(ISS) in Chinese Han populations. Methods Case-control method was employed,and 199 children with ISS(ISS group) and 469 adults with normal weight(control group) were enrolled.Genotyping and comparison were performed in 16 SNP sites of GHR gene,positive SNP sites(significant differences in specific genotypic frequency) were screened,and the associations of genotypes of positive SNP sites with risks of ISS and related clinical variables such as serum insulin-like growth factor 1(IGF-1)were analysed. Results Three positive SNP sites of rs6182(P=0.027),rs4410646(P=0.01) and rs10044169(P=0.024)were found in ISS group and control group.For rs6182(G/T),the risk of ISS of genotype TT and genotype GT decreased under T dominant mode(OR=0.624,95%CI:0.402-0.969,P=0.021).For rs4410646(A/C),the risk of ISS of genotype AA decreased under C dominant mode(OR=0.674,95%CI:0.475-0.958,P=0.016).Multivariate Logistics regression analysis of this site revealed that serum IGF-1 was related to genotype AA(OR=1.011,95%CI:1.002-1.020,P=0.018) and genotype CA(OR=1.010,95%CI:1.001-1.019,P=0.037) with genotype CC as reference,and serum IGF-1 was related to genotype CC(OR=0.989,95%CI:0.980-0.998,P=0.018) with genotype AA as reference.For rs10044169(A/C),the risk of ISS of genotype CC and genotype CA significantly decreased(OR=0.649,95%CI:0.424-0.993,P=0.027) under C dominant mode. Conclusion GHR plays a role in the growth promotion effect mediated by growth hormone,and 3 SNP sites of human GHR gene may be related to genetic susceptibility to ISS.

Objective To explore the possible role of growth hormone receptor(GHR) gene exon 10 in the etiology of idiopathic short stature(ISS).Methods Thirty children with ISS were chosen as ISS group and 30 cases of healthy children as the healthy control group,diagnosed in the Children′s Hospital Affiliated to Soochow University during Sep.2008 to Jul.2009.Two mL venous blood was withdraw,genomic DNA was extracted,amplification of GHR exon 10 sequence was performed by application of polymer polymerase chain reaction(PCR),and PCR products were purified for DNA sequencing,and the detected sequences were compared with the ones published by United States National Center for Biotechnology Information(national center for biotechnology information,NCBI),and the allele frequency and genotype frequency in case group and control group were statistically analyzed using χ2 test by the SAS 8.0 statistical software.Results GHR gene exon 10 had 2 single nucleotide polymorphism(SNP) loci,site 685 and site 790.On site 685,base A mutated heterozygously to base C,resulting in the No.526 amino acid changed to proline from histidine,or I526L.This site existed 3 genotypes(AA,CA,CC),by comparison of the genotype frequency and allele frequency between subjects in 2 comparison groups had no statistical significance(Pa0.05).The base C he-terozygously mutated to base A on site 790,resulting in the No.561 amino acid changed to aspartic acid from alanine,or P561T.This site existed 2 genotypes(CC,CA),and the genotype frequency and allele frequency had no statistical significance between the 2 groups(Pa0.05).Conclusion The SNPs on site 685 and site 790 of GHR gene exon 10 are not concerned with the morbility of ISS.