AUTHOR=Li Lele , Gao Fenqi , Fan Lijun , Su Chang , Liang Xuejun , Gong ChunXiu 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2020.582516

DOI=10.3389/fendo.2020.582516

ISSN=1664-2392

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