Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai, China.
Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
Mol Genet Genomic Med. 2022 Jan;10(1):e1820. doi: 10.1002/mgg3.1820. Epub 2021 Nov 29.
Premature ovarian insufficiency (POI) is a highly heterogeneous disease, and up to 25% of cases can be explained by genetic causes. The transcription factor WT1 has long been reported to play a crucial role in ovary function. Wt1-mutated female mice exhibited POI-like phenotypes.
In this study, whole exome sequencing (WES) was applied to find the cause of POI in Han Chinese women. A nonsense variant in the WT1 gene: NM_024426.6:c.1387C>T(p.R463*) was identified in a non-syndromic POI woman. The variant is a heterozygous de novo mutation that is very rare in the human population. The son of the patient inherited the mutation and developed Wilms' tumor and urethral malformation at the age of 7. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, the novel variant is categorized as pathogenic. Western blot analysis further demonstrated that the WT1 variant could produce a truncated WT1 isoform in vitro.
A rare heterozygous nonsense WT1 mutant is associated with non-syndromic POI and Wilms' tumor. Our finding characterized another pathogenic WT1 variant, providing insight into genetic counseling.
卵巢早衰（POI）是一种高度异质性的疾病，多达 25%的病例可以用遗传原因来解释。转录因子 WT1 长期以来被报道在卵巢功能中起着至关重要的作用。Wt1 突变的雌性小鼠表现出类似于 POI 的表型。
在这项研究中，我们应用外显子组测序（WES）来寻找中国汉族女性 POI 的病因。在一名非综合征性 POI 女性中发现了 WT1 基因中的一个无义变异：NM_024426.6:c.1387C>T(p.R463*)。该变异是杂合性的新生突变，在人群中非常罕见。患者的儿子遗传了该突变，并在 7 岁时患上了肾母细胞瘤和尿道畸形。根据美国医学遗传学与基因组学学会和分子病理学协会（ACMG/AMP）指南，该新变异被归类为致病性的。Western blot 分析进一步表明，WT1 变异在体外可以产生一种截断的 WT1 异构体。
一种罕见的杂合性无义 WT1 突变与非综合征性 POI 和肾母细胞瘤有关。我们的发现描述了另一种致病性的 WT1 变异，为遗传咨询提供了依据。
