一例早发性卵巢功能不全患者的ATG7新发变异分析

Analysis of ATG7 de novo Variant in a Patient Affected by Premature Ovarian Insufficiency

早发性卵巢功能不全(POI)是女性生育力下降的重要原因之一.POI的病因复杂多样,大部分患者的病因仍待研究,其中遗传因素占POI病因的20%~25%.本研究通过全外显子组测序(WES)技术在一位汉族散发POI患者中发现ATG7基因的杂合c.1372G>A(p.V458M)变异.ATG7(autophagy-related 7)是自噬相关基因,已有研究揭示该基因缺陷可导致小鼠出现POI表型.本研究发现的ATG7 c.1372G>A变异在千人基因组、ExAC和gnomAD 3个数据库的东亚人群中均无报道,SIFT、PolyPhen-2、MutationTaster和CADD 4种不同算法均预测其有害.根据美国医学遗传学和基因组学会发布的序列变异解读标准与指南,该变异属于致病变异.家系回访揭示该变异属于新发变异,健康父母均为野生型纯合子.生物信息学预测发现该变异对应的氨基酸位于蛋白质的α螺旋区域,且在多物种中高度保守,提示该变异很可能诱导蛋白质功能受损.

Premature Ovarian Insufficiency(POI)is one of the major causes of reduced female fertility.The genetic factors account for approximately 20%—25%of the POI patients.However,causative genes involved in the majority of POI patients remain to be identified due to high heterogeneity in POI etiology.Here,a rare heterozygous missense variant in ATG7(autophagy-related 7):c.1372G>A(p.V458M)was identified in a Han Chinese patient with POI through whole-exome sequencing(WES).ATG7 is an autophagy-related gene,and the loss of Atg7 in ovaries could cause POI phenotype in mice.The c.1372G>A variant is absent in East Asian populations of 1000 Genome,ExAC and gnomAD.It is predicted to be deleterious by all four bioinformatics tools including SIFT,Polyphen-2,MutationTaster and CADD.It is also classified to be likely pathogenic following the American College of Medical Genetics(ACMG)guidelines.Healthy parents of the POI patient are both wild-type homozygotes so this variant is de novo.The altered amino acid is highly conserved in various species.Bioinformatics methods predicted that it is located in anα-helix region of ATG7 protein,which is probably essential for the structure and function of ATG7.