{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T03:11:22Z","timestamp":1783653082867,"version":"3.55.0"},"reference-count":24,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD098458"],"award-info":[{"award-number":["R01HD098458"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Mediator complex subunit 12 (MED12) is required for the assembly of the kinase module of Mediator, a regulatory complex that controls the formation of the RNA polymerase II\u2010mediated preinitiation complex. <jats:italic>MED12<\/jats:italic>\u2010related disorders display unique gender\u2010specific genotype\u2013phenotype associations and include X\u2010linked recessive Opitz\u2013Kaveggia syndrome, Lujan\u2013Fryns syndrome, Ohdo syndrome, and nonspecific intellectual disability in males predominantly carrying missense variants, and X\u2010linked dominant Hardikar syndrome and nonspecific intellectual disability in females known to predominantly carry de novo nonsense\/frameshift and nonsense\/missense variants, respectively. <jats:italic>MED12<\/jats:italic> was previously identified as a low\u2010penetrance candidate gene for non\u2010isolated congenital diaphragmatic hernia (CDH+). At the time, however, there was insufficient evidence to confirm this association. In a clinical database search, we identified 18 individuals who were molecularly diagnosed with <jats:italic>MED12<\/jats:italic>\u2010related disorders by exome or genome sequencing, including eight missense, four frameshift, two nonsense, and one splice variant. Nine of these variants have not been previously reported. Two females with nonspecific intellectual disability were found to carry a de novo frameshift variant, indicating that potentially truncating variants causing nonspecific intellectual disability are not limited to nonsense variants. Notably, CDH was reported in three out of seven females with Hardikar syndrome or nonspecific intellectual disability but was not reported in males with <jats:italic>MED12<\/jats:italic>\u2010related disorders. These results suggest that pathogenic <jats:italic>MED12<\/jats:italic> variants are a cause of CDH+ in females with Hardikar syndrome and nonspecific intellectual disability.<\/jats:p>","DOI":"10.1002\/ajmg.a.63868","type":"journal-article","created":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T06:48:55Z","timestamp":1725086935000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<i>MED12<\/i> Loss\u2010of\u2010Function Variants as a Cause of Congenital Diaphragmatic Hernia in Females With Hardikar Syndrome and Nonspecific Intellectual Disability"],"prefix":"10.1002","volume":"197","author":[{"given":"Eric C.","family":"Kao","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Baylor Genetics  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Mizerik","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos A.","family":"Bacino","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzheng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Baylor Genetics  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"Vossaert","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Baylor Genetics  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1460-5169","authenticated-orcid":false,"given":"Daryl A.","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.6594"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36183"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.00425"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62919"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320440105"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36162"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010020\u201001031\u20107"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320170124"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2022.01.002"},{"key":"e_1_2_9_11_1","volume-title":"GeneReviews\u00ae","author":"Lyons M. 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