Variants of and May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of .

Variants of are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the gene. We tested the transactivation activity of novel variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes , and in three individuals. Our study increases the number of variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous variation.