WT1: A single gene associated with multiple and severe phenotypes

The Wilms tumor suppressor gene (WT1) is a transcription factor with a wide array of functions, that affects the differentiation and survival of several cell types in different organs. It plays a special role in renal and gonadal development, organs in which WT1 deleterious variants determine well-established conditions, such as Wilms tumor, corticosteroid-resistant nephropathy with progression to loss of renal function, and a spectrum of gonadal development abnormalities (XX and XY gonadal dysgenesis, XX testicular and XX ovotesticular) and testicular tumors. Moreover, WT1 variants are also associated with urinary tract malformations, heart and nervous system diseases, diaphragmatic hernias, leukemia, and tumorigenesis. Consequently, an increasingly broad phenotypic spectrum has been associated with WT1 deleterious variants in 46,XX, and 46,XY individuals. The genotype-phenotype causal relationship involving WT1 pathogenic variants and their heterogeneous clinical manifestations is also discussed.