A de novo loss-of-function (LoF) variant in the KMT5B gene (previously known as SUV420H1) was identified in an autistic proband from a simplex family in Iossifov et al., 2012 (PMID 22542183). In addition, two missense variants in the KMT5B gene that were predicted to be deleterious was also identified in ASD probands from the Simons Simplex Collection in Sanders et al., 2012 (PMID 22495306). Although population rate is not provided, many missense variants are listed in the NHLBI Exome Sequencing Project's Exome Variant Viewer for this gene. Two additional de novo LoF variants in this gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified KMT5B as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo variants in KMT5B have been identified in individuals with ASD and/or developmental delay/intellectual disability (Stessman et al., 2017; Yuen et al., 2017).
Histone methyltransferase that specifically trimethylates 'Lys-20' of histone H4. H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2). Plays a role in myogenesis by regulating the expression of target genes, such as EID3.
Type of Disorder
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
Hmt4-20-Gal4 driver line expressing UAS-Hmt4-20-RNAi.
Allele Type: Loss-of-function
Strain of Origin: Not reported
Genetic Background: Not reported
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: When challenged in the light-off jump paradigm, the mutants showed a habituation deficit compared to controls.
Exp Paradigm: Habituation was measured in number of trials to reach no-jump criterion.