The MED12L gene is located on chromosome 3 at 3q25.1 and encodes for the 2145-amino acid mediator complex subunit 12-like (MED12L) protein, one of the subunits in the CDK8 kinase module of the Mediator complex.. The Mediator complex is a large multiprotein complex consisting of four different modules (Head, Middle, Tail and CDK8 kinase) and 26 subunits. The Mediator complex plays a key regulator of gene expression involved in cell growth, homeostasis, development and differentiation. MED12L was first reported in relation to autosomal dominant Nizon-Isidor syndrome in 2019 (Nizon et al 2019, PMID: 31155615).
Evidence supporting this gene-disease relationship includes case-level and experimental data. Six heterozygous variants (1 missense, 1 nonsense, 2 frameshift, and 2 splice-site variants) in MED12L that have been reported in at least 9 unrelated patients with clinical features suggestive of autosomal dominant Nizon-Isidor syndrome in 3 publications (Nizon et al 2019, PMID: 31155615; Park et al 2022, PMID: 36212160; Ferraz et al 2022, PMID: 35920825) are included in this curation. This gene-disease relationship is also supported by biochemical function, gene expression studies, and protein interaction data (Maalouf et al 2024, PMID: 38943827; Daniels et al 2013; Vogl et al 2013, PMID:23575864). In summary, there is definitive evidence supporting the relationship between MED12L and autosomal dominant Nizon-Isidor syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date November 19th, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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