Disorders of Sex Development in Individuals Harbouring Variants: WES and Interactome Evidence of Oligogenic Inheritance.

Mastermind-like domain-containing 1 (MAMLD1) has been shown to play an important role in the process of sexual development and is associated with 46,XY disorders of sex development (DSDs). However, the causative role of variations in DSDs remains disputable. In this study, we have described a clinical series on children from unrelated families with 46,XY DSD harbouring variants. Whole exome sequencing (WES) was performed for each patient. WES data were filtered using common tools and disease customisation algorithms, including comparison against lists of known and candidate MAMLD1-related and DSD-related genes. Lastly, we investigated the hypothesis that MAMLD1-related DSD may follow an oligogenic mode of inheritance. Forty-three potentially deleterious/candidate variants of 18 genes (, , , , , , , , , , , , , , , , , and ) were identified, which may have contributed to the patient phenotypes. was the most commonly identified gene. Specific gene combinations were also identified. In the interactome analysis, exhibited direct connection with // and /. Through , the following eight genes were shown to be associated with :, , , , , and . Our findings provide further evidence that individuals with MAMLD1-related 46,XY DSD could carry two or more variants of known DSD-related genes, and the phenotypic outcome of affected individuals might be determined by multiple genes.