Submission Details

The KMT2A gene is located on chromosome 11 at 11q23.3 and encodes the lysine methyltransferase 2A with histone H3 lysine 4 (H3K4) methyltransferase activity. KMT2A was first reported in relation to autosomal dominant Wiedemann-Steiner syndrome in 2000 (Steiner et al., PMID: 10826636). Characteristic features for this disorder include mild to profound intellectual disability, musculoskeletal anomalies, distinctive facial features, hypertrichosis cubiti, short stature, and behavioral issues. Additional features include alterations of the corpus callosum, growth restriction, failure to thrive, feeding difficulties, cardiac anomalies, micrognathia, high arched palate, and dental anomalies. At least 8 unique variants (including frameshift, stop-gained, and missense variants) have been reported in 8 probands in 4 publications (Jones et al., 2012, PMID: 22795537; Miyake et al., 2016, PMID: 25810209; Baer et al., 2018, PMID: 29574747; Lebrun et al., 2018, PMID: 29203834) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be de novo loss of function variants but de novo missense variants have also been reported. This disorder presents with a widely variable phenotype. This gene-disease association is also supported by mouse models and expression studies (Yu et al., 1995, PMID: 7477409; Ayton et al., 2001, PMID: 11536426, Wang et al., 2009, PMID: 19703992). In summary, KMT2A is definitively associated with autosomal dominant Wiedemann-Steiner 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 Gene Curation Expert Panel on the meeting date 02.23.2022 (SOP Version 8).