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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  MAMLD1  variations in DSDs remains disputable. In this study, we have described a clinical series on children from unrelated families with 46,XY DSD harbouring  MAMLD1  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 ( RET ,  CDH23 ,  MYO7A ,  NOTCH2 ,  MAML1 ,  MAML2 ,  CYP1A1 ,  WNT9B ,  GLI2 ,  GLI3 ,  MAML3 ,  WNT9A ,  FRAS1 ,  PIK3R3 ,  FREM2 ,  PTPN11 ,  EVC , and  FLNA ) were identified, which may have contributed to the patient phenotypes.  MYO7A  was the most commonly identified gene. Specific gene combinations were also identified. In the interactome analysis,  MAMLD1  exhibited direct connection with  MAML1 / 2 / 3  and  NOTCH1 / 2 . Through  NOTCH1/2 , the following eight genes were shown to be associated with  MAMLD1 : WNT9A/9B ,  GLI2/3 ,  RET ,  FLNA ,  PTPN11 , and  EYA1 . 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.

Disorders of Sex Development in Individuals Harbouring MAMLD1 Variants: WES and Interactome Evidence of Oligogenic Inheritance