摘　要：为探讨1例高促性腺激素闭经同时卵巢功能正常的不孕患者的遗传学病因，同时也为遗传咨询以及生育指导提供依据，应用全外显子组测序技术对患者临床表征相关的基因进行生物信息学分析及诊断，对患者及其姐姐、弟弟与父母的FSHR基因进行变异位点Sanger测序。结果检出，患者FSHR基因第5外显子c.392G>A（p.Gly131Asp）及第4外显子c.310A>G（p.Lys104Glu）的复合杂合变异，母亲携带c.392G>A（p.Gly131Asp）的杂合变异，父亲携带c.310A>G（p.Lys104Glu）的杂合变异。姐姐和弟弟检出与患者相同的FSHR基因复合杂合变异。通过家系分析及依据美国医学遗传学与基因组学学会（ACMG）指南对变异进行分类得出，2个错义突变均为可能致病性突变。临床数据以及文献回顾显示，该患者应为卵巢抵抗综合征（ROS）而非卵巢早衰（POF）。本研究发现，FSHR基因复合杂合变异是导致患者及其姐姐原发性闭经以及不孕的可能遗传学病因。不孕不育是遗传异质性非常高的一类疾病，临床很难通过常规检测来对其进行区分，基因检测对这类疾病的检测具有重要意义。同时，已报道的中国人群FSHR基因的致病性变异较少。本文卵巢抵抗综合征家系中FSHR基因2个新变异位点的检出，丰富了FSHR基因突变谱，对于未来该疾病的诊断具有重要的参考意义。
关键词：FSHR基因；复合杂合变异；不孕；卵巢抵抗综合征；原发性闭经
中图分类号：R711.6　　　　　　文献标志码：ADOI：10.3969/j.issn.1007-7146.2021.04.012

Abstract: To explore the genetic basis of a patient with hypergonadotropic amenorrhea and normal number of antral follicles, and provide a basis for genetic counseling and direction for reproduction, the proband was subjected to whole exome sequencing and her sister, brother and parents performed sanger sequencing on FSHR gene mutation loci. We applied the bioinformatics analysis according to clinical characterization of the patient. The proband was found to harbor compound heterozygous variants of the FSHR gene in exon 5 c.392G>A (p.Gly131Asp) and exon 4 c.301A>G (p.Lys104Glu), which were respectively inherited from her mother and father. The sister and brother were found to have the same FSHR gene complex heterozygous variation as the patient. Pedigree and bioinformatic analysis suggested that both mutations were likely pathogenic according to the ACMG guidelines. The clinical data and literature review suggested that the patient was affected with resistant ovary syndrome rather than premature ovarian failure. In this study, FSHR gene compound heterozygous variation was identified as a possible genetic cause of primary amenorrhea and infertility in the patient and her sister. Infertility is a kind of disease with very high genetic heterogeneity, and it is difficult to distinguish the diseases by routine detection in clinical practice. Genetic detection is of great significance for the detection of such diseases. At the same time, few pathogenic variants of FSHR gene have been reported in Chinese population. The detection of two new mutation sites of FSHR gene in the family of ovarian resistance syndrome in this paper enriches the mutation spectrum of FSHR gene, which has important reference significance for the diagnosis of this disease in the future.
Key words: FSHR gene; compound heterozygous variant; infertility; resistant ovary syndrome; primary amenorrhea
（Acta Laser Biology Sinica, 2021, 30(4): 378-384）