Abstract
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.
Highlights
Disorders of sex development (DSDs) comprise a group of congenital diseases associated with the atypical development of internal and external genital structures
We investigated the hypothesis that Mastermind-like domain-containing 1 gene (MAMLD1)-related DSDs may follow an oligogenic mode of inheritance
An adequate response of T levels to human chorionic gonadotropin stimulation was observed in patients #1–3, #6, and #8
Summary
Disorders of sex development (DSDs) comprise a group of congenital diseases associated with the atypical development of internal and external genital structures. Mastermind-like domain-containing 1 gene (MAMLD1), known as chromosome X open reading frame 6 (CXorf6) or F18 (online Mendelian inheritance in man (OMIM)# 300120), was first reported in two cases of myotubular myopathy and male hypogenitalism [6, 7]. It was identified as a suitable candidate gene in patients with 46,XY DSD and was shown to be expressed in foetal Leydig cells at a time point close to the critical period for sex development [8, 9]. MAMLD1 appears to play an important role during sex development and is associated with 46, XY DSD
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