Human Gene Module / Chromosome 1 / KLHL20

KLHL20kelch like family member 20

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
6 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1q25.1
Associated Disorders
-
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
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to KLHL20 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Lee YR , et al. (2010) No -
2 Support - Lin MY et al. (2011) No -
3 Primary Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Recent Recommendation - Sleyp Y et al. (2022) Yes ADHD, stereotypy
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1069G>A p.Gly357Arg missense_variant De novo - - 36214804 Sleyp Y et al. (2022)
c.1069G>A p.Gly357Arg missense_variant Unknown - - 36214804 Sleyp Y et al. (2022)
c.1214G>A p.Ser405Asn missense_variant De novo - - 36214804 Sleyp Y et al. (2022)
c.1262A>G p.Gln421Arg missense_variant De novo - - 36214804 Sleyp Y et al. (2022)
c.1777G>T p.Gly593Trp missense_variant De novo - - 36214804 Sleyp Y et al. (2022)
c.1214G>A p.Ser405Asn missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

1/1/2023
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1

Increased from to 1

Krishnan Probability Score

Score 0.45050682594323

Ranking 10865/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.06167708222994

Ranking 8342/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94062517080805

Ranking 14635/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.075243955436635

Ranking 11381/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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