Whole exome sequencing identified a rare WT1 loss‐of‐function variant in a non‐syndromic POI patient

Abstract Background 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. Methods and Results 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. Conclusions 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.