Submission Details

Autosomal dominant

12/10/2019

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 an autosomal dominant neurodevelopmental disorder in 2017 (28191889: Stessman et al. 2017), although de novo variants had been reported earlier (25363768: Iossifov et al. 2014; 27479843: Lelieveld et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven unique variants (four frameshift, one stop-gained, one canonical splice, and one missense) identified in seven cases from three publications (19344873: Firth et al. 2009; 27479843: Lelieveld et al. 2016; 28191889: Stessman et al. 2017). No segregation evidence was available, and five of the variants occurred de novo. The mechanism of disease has not yet been clearly established, but haploinsufficiency has been suggested. This gene-disease relationship is also supported by a shared function with other genes associated with neurodevelopmental disorders, expression in the brain in a temporally and spatially regulated manner that correlates with neurogenesis, and a Drosophila knockdown model that shows impaired habituation in a behavioral assay (28191889: Stessman et al. 2017). In summary, there is strong evidence to support the relationship between KMT5B and autosomal dominant KMT5B-related neurodevelopmental disorder. Additional reports in humans published more than three years since the first proposal are needed to reach a definitive classification.

27479843 28191889 19344873