{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T20:17:50Z","timestamp":1780604270596,"version":"3.54.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005089","name":"Beijing Municipal Natural Science Foundation","doi-asserted-by":"publisher","award":["7204260"],"award-info":[{"award-number":["7204260"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats: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 <jats:italic>MAMLD1<\/jats: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 <jats:italic>MAMLD1<\/jats: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 (<jats:italic>RET<\/jats:italic>, <jats:italic>CDH23<\/jats:italic>, <jats:italic>MYO7A<\/jats:italic>, <jats:italic>NOTCH2<\/jats:italic>, <jats:italic>MAML1<\/jats:italic>, <jats:italic>MAML2<\/jats:italic>, <jats:italic>CYP1A1<\/jats:italic>, <jats:italic>WNT9B<\/jats:italic>, <jats:italic>GLI2<\/jats:italic>, <jats:italic>GLI3<\/jats:italic>, <jats:italic>MAML3<\/jats:italic>, <jats:italic>WNT9A<\/jats:italic>, <jats:italic>FRAS1<\/jats:italic>, <jats:italic>PIK3R3<\/jats:italic>, <jats:italic>FREM2<\/jats:italic>, <jats:italic>PTPN11<\/jats:italic>, <jats:italic>EVC<\/jats:italic>, and <jats:italic>FLNA<\/jats:italic>) were identified, which may have contributed to the patient phenotypes. <jats:italic>MYO7A<\/jats:italic> was the most commonly identified gene. Specific gene combinations were also identified. In the interactome analysis, <jats:italic>MAMLD1<\/jats:italic> exhibited direct connection with <jats:italic>MAML1<\/jats:italic>\/<jats:italic>2<\/jats:italic>\/<jats:italic>3<\/jats:italic> and <jats:italic>NOTCH1<\/jats:italic>\/<jats:italic>2<\/jats:italic>. Through <jats:italic>NOTCH1\/2<\/jats:italic>, the following eight genes were shown to be associated with <jats:italic>MAMLD1<\/jats:italic>:<jats:italic>WNT9A\/9B<\/jats:italic>, <jats:italic>GLI2\/3<\/jats:italic>, <jats:italic>RET<\/jats:italic>, <jats:italic>FLNA<\/jats:italic>, <jats:italic>PTPN11<\/jats:italic>, and <jats:italic>EYA1<\/jats: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.<\/jats:p>","DOI":"10.3389\/fendo.2020.582516","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T13:14:41Z","timestamp":1608729281000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Disorders of Sex Development in Individuals Harbouring MAMLD1 Variants: WES and Interactome Evidence of Oligogenic Inheritance"],"prefix":"10.3389","volume":"11","author":[{"given":"Lele","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenqi","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ChunXiu","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.bpobgyn.2017.11.005","article-title":"Disorders of Sex Development","volume":"48","author":"Witchel","year":"2018","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0010-8","article-title":"COST Action BM1303 working group 1. 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