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Relevance to Autism

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).

Molecular Function

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.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
ASD
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
DD, ID
ASD, epilepsy/seizures
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ID
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
ASD
Support
De novo gene disruptions in children on the autistic spectrum.
ASD
Recent Recommendation
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Recent Recommendation
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.
ASD, DD, ID
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Incorporating Functional Information in Tests of Excess De Novo Mutational Load.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN336R001 
 missense_variant 
 c.791G>C 
 p.Trp264Ser 
 De novo 
  
 Simplex 
 GEN336R002 
 missense_variant 
 c.1538C>T 
 p.Ala513Val 
 De novo 
  
 Simplex 
 GEN336R003 
 splice_site_variant 
 c.977+1G>A 
  
 De novo 
  
 Simplex 
 GEN336R004 
 stop_gained 
 c.2347C>T 
 p.Arg783Ter 
 De novo 
  
 Simplex 
 GEN336R005 
 frameshift_variant 
 c.555_558del 
 p.Tyr185fs 
 De novo 
  
 Simplex 
 GEN336R006 
 missense_variant 
 c.2548A>G 
 p.Ile850Val 
 Unknown 
  
 Unknown 
 GEN336R007 
 missense_variant 
 c.1619G>A 
 p.Arg540Gln 
 Familial 
 Maternal 
  
 GEN336R008 
 frameshift_variant 
 c.725del 
 p.Leu242HisfsTer30 
 De novo 
  
  
 GEN336R009 
 frameshift_variant 
 c.1557_1558del 
 p.Asn520SerfsTer33 
 De novo 
  
  
 GEN336R010 
 frameshift_variant 
 c.1166dup 
 p.Asn389LysfsTer6 
 Unknown 
  
  
 GEN336R011 
 missense_variant 
 c.676G>A 
 p.Asp226Asn 
 De novo 
  
  
 GEN336R012 
 frameshift_variant 
 :c.953_1028del;c.1157_1232del;c.1673_1748del 
 p.Pro318fs;p.Pro386fs;p.Pro558fs 
 De novo 
  
 Multiplex 
 GEN336R013 
 missense_variant 
 c.1876T>C;c.2080T>C;c.2596T>C 
 p.Ser626Pro;p.Ser694Pro;p.Ser866Pro 
 De novo 
  
 Simplex 
 GEN336R014 
 stop_gained 
 c.1981G>T 
 p.Glu661Ter 
 De novo 
  
  
 GEN336R015 
 frameshift_variant 
 c.219delC 
 p.Ala74ProfsTer10 
 De novo 
  
  
 GEN336R016 
 stop_gained 
 c.559C>T 
 p.Arg187Ter 
 De novo 
  
  
 GEN336R017 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN336R018 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN336R019 
 splice_site_variant 
 c.978-1G>A 
 p.? 
 Familial 
 Maternal 
 Simplex 
 GEN336R020 
 frameshift_variant 
 c.1205_1206insGCGTAAAA 
 p.Lys402fs 
 Familial 
 Paternal 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion-Duplication
 1
 
11
Deletion-Duplication
 18
 
11
Deletion
 1
 
11
Deletion
 2
 

Model Summary

Hmt4-20 mutants showed a habituation deficit.

References

Type
Title
Author, Year
Primary
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.

F_Hmt4-20_1_KD_Gal4:UAS;RNAi-VDRC106849

Model Type: Genetic
Model Genotype: Wild type
Mutation: 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:

F_Hmt4-20_1_KD_Gal4:UAS;RNAi-VDRC106849

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Habituation to aversive stimuli1
Decreased
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.
 Light-off startle jump
 adult stage
Startle response1
 No change
 Light-off startle jump
 adult stage
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Seizure, Sensory, Social behavior

No PIN Data Available
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