Submission Details

The KMT5B gene, which was previously known as SUV420H1, is located on chromosome 11 at 11q13.2 and encodes lysine methyltransferase 5B. Through its role as a histone methyltransferase, KMT5B 'writes' H4K20 methylation marks and regulates transcription. KMT5B was first reported in relation to autosomal dominant neurodevelopmental disorders in 2017 (Stessman et al., PMID:28191889), although de novo variants had been reported earlier (Iossifov et al., 2014, PMID: 25363768; Lelieveld et al., 2016, PMID: 27479843). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Nine unique variants (6 frameshift, 1 nonsense, 1 canonical splice, and 1 missense) have been reported in nine probands from three publications ( Stessman et al., 2017, PMID:28191889; Faundes et al., 2018, PMID: 29276005; Trinh et al., 2019, PMID 31238879). Eight of the variants occurred de novo, while the other was. The mechanism of disease has not yet been clearly established, but haploinsufficiency has been suggested. This gene-disease relationship is also supported by shared function with other genes associated with neurodevelopmental disorders (PMID: 28191889). A Drosophila knockdown model shows impaired habituation in a behavioral assay (PMID: 28191889) and heterozygous KMT5B knockout mice show smaller body and brain size and deficits in neonatal reflexes, sociability, stress-induced grooming, and behaviors related to anxiety, depression, and fear learning (Wickramasekara et al., 2021, PMID 33871180). In summary, KMT5B is definitively associated with autosomal dominant KMT5B-related neurodevelopmental disorders. 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 11.03.2021 (SOP Version 8).