目的 分析1例性发育异常(DSD)患儿的临床特征，探讨其遗传学病因。 方法 选取2019年7月29日因原发闭经就诊于临沂市人民医院遗传咨询门诊的1例DSD患儿作为研究对象，收集其临床资料。应用染色体核型分析及实时荧光定量PCR检测Y染色体微缺失，分析患儿染色体是否存在异常。利用高通量测序对患儿及父母进行基因检测，对候选变异进行Sanger测序验证，对变异位点进行致病性评估。 结果 患儿年龄为13岁，社会性别女，存在原发性闭经，男性第二性征发育，超声检查未探及子宫及明确卵巢结构，可探及窄带样阴道低回声及弯曲阴茎海绵体样结构。患儿染色体核型为46, XY，Y染色体AZF区段不存在缺失。基因测序发现患儿存在母源的NR5A1：c.323delA(p.Q108Rfs*188)。根据美国医学遗传学与基因组学学会(ACMG)遗传变异分类标准与指南，NR5A1：c.323delA变异评级为致病性变异(PVS1＋PM2_Supporting＋PP4)。 结论 NR5A1：c.323delA变异考虑是该DSD患儿的致病原因，为临床诊断和治疗提供遗传学依据。 Objective To analyze the clinical features and genetic basis of a child with Disorder of sex development (DSD). Methods A child who was admitted to the Linyi People′s Hospital for primary amenorrhoea on July 29, 2019 was selected as the study subject. Clinical data of the child was collected. Chromosomal karyotyping and quantitative real-time PCR were used to detect Y chromosome microdeletions and other chromosomal aberrations. Next-generation sequencing was carried out for the child and her parents. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Results The child, a 13-year-old girl, has featured primary amenorrhoea and onset of secondary sex characteristics of males. Ultrasound exam had detected no uterus and definite ovarian structure, but narrow band vaginal hypoecho and curved cavernoid structure. The child was found to have a 46, XY karyotype without an AZF deletion. DNA sequencing revealed that she has harbored a maternally derived c. 323delA (p.Q108Rfs*188) variant in the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene, which may result in a truncated protein. The variant was classified as pathogenic (PVS1+ PM2_Supporting+ PP4) based on the guidelines from the American College of Medical Genetics and Genomics. Conclusion The NR5A1: c. 323delA variant probably underlay the pathogenesis of 46, XY DSD in this child. The discovery of the novel variant has enriched the mutational spectrum of NR5A1 gene and provided a basis for clinical diagnosis, treatment and prenatal diagnosis.
Genetic analysis of a child with 46, XY Disorder of sex development due to a novel variant ofNR5A1 gene
Objective To analyze the clinical features and genetic basis of a child with Disorder of sex development (DSD). Methods A child who was admitted to the Linyi People′s Hospital for primary amenorrhoea on July 29, 2019 was selected as the study subject. Clinical data of the child was collected. Chromosomal karyotyping and quantitative real-time PCR were used to detect Y chromosome microdeletions and other chromosomal aberrations. Next-generation sequencing was carried out for the child and her parents. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Results The child, a 13-year-old girl, has featured primary amenorrhoea and onset of secondary sex characteristics of males. Ultrasound exam had detected no uterus and definite ovarian structure, but narrow band vaginal hypoecho and curved cavernoid structure. The child was found to have a 46, XY karyotype without an AZF deletion. DNA sequencing revealed that she has harbored a maternally derived c. 323delA (p.Q108Rfs*188) variant in the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene, which may result in a truncated protein. The variant was classified as pathogenic (PVS1+ PM2_Supporting+ PP4) based on the guidelines from the American College of Medical Genetics and Genomics. Conclusion The NR5A1: c. 323delA variant probably underlay the pathogenesis of 46, XY DSD in this child. The discovery of the novel variant has enriched the mutational spectrum of NR5A1 gene and provided a basis for clinical diagnosis, treatment and prenatal diagnosis.
Sex chromosome disorders of sex developmentNR5A1 geneReal-Time PCRChild
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