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Relevance to Autism

A de novo missense variant in the KLHL20 gene was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020. Sleyp et al., 2022 described 14 patients with de novo missense variants in the KLHL20 gene presenting with a neurodevelopmental syndrome characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder or autistic features, hyperactivity, and subtle dysmorphic facial features; a recurrent de novo missense variant (NM_014458.4:c.1069G>A;p.Gly357Arg) was observed in 11 patients.

Molecular Function

The protein encoded by this gene is a substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in interferon response and anterograde Golgi to endosome transport. The BCR(KLHL20) E3 ubiquitin ligase complex mediates the ubiquitination of DAPK1, leading to its degradation by the proteasome, thereby acting as a negative regulator of apoptosis (Lee et al., 2010). The BCR(KLHL20) E3 ubiquitin ligase complex also acts as a regulator of neurite outgrowth by mediating ubiquitination and degradation of PDZ-RhoGEF/ARHGEF11 (Lin et al., 2011).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth
Support
The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses.
Recent Recommendation
De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
ASD or autistic features, DD, ID, epilepsy/seizure
ADHD, stereotypy
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1363R001 
 missense_variant 
 c.1214G>A 
 p.Ser405Asn 
 De novo 
  
  
 GEN1363R002 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R003 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R004 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R005 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R006 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R007 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R008 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R009 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R010 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R011 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 De novo 
  
  
 GEN1363R012 
 missense_variant 
 c.1069G>A 
 p.Gly357Arg 
 Unknown 
  
  
 GEN1363R013 
 missense_variant 
 c.1214G>A 
 p.Ser405Asn 
 De novo 
  
  
 GEN1363R014 
 missense_variant 
 c.1262A>G 
 p.Gln421Arg 
 De novo 
  
  
 GEN1363R015 
 missense_variant 
 c.1777G>T 
 p.Gly593Trp 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
1
Duplication
 44
 
1
Duplication
 1
 
1
Deletion
 1
 
1
Duplication
 1
 
1
Deletion
 2
 
1
Deletion
 2
 
1
Deletion
 2
 
1
Deletion
 2
 
1
Deletion-Duplication
 13
 

No Animal Model Data Available

 

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