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Intellectual disability
Gene: KDM5A

KDM5A (lysine demethylase 5A)
EnsemblGeneIds (GRCh38): ENSG00000073614
EnsemblGeneIds (GRCh37): ENSG00000073614
OMIM: 180202, Gene2Phenotype
KDM5A is in 3 panels

7 reviews

Eleanor Williams (Genomics England Curator)

This gene is not currently associated with a disease phenotype in OMIM, but checked PMID:33350388 to make sure it is the same gene listed in the publication as on this panel and it is, so added the gene-checked tag
Created: 16 Oct 2023, 7:44 p.m. | Last Modified: 16 Oct 2023, 7:44 p.m.

Panel Version: 5.313

Created: 16 Oct 2023, 7:44 p.m.
Last Modified: 16 Oct 2023, 7:44 p.m.
Panel version: 5.313

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.

Panel Version: 5.286

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Created: 11 Oct 2023, 9:34 a.m.
Last Modified: 11 Oct 2023, 9:34 a.m.
Panel version: 5.286

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification:, There is sufficient evidence for this gene to be promoted to GREEN at the next major review.

This gene can be associated with both monoallelic and biallelic inheritance as there are at least three cases each for both of them.
Created: 11 Apr 2023, 4:52 p.m. | Last Modified: 11 Apr 2023, 5:11 p.m.

Panel Version: 5.25

PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Created: 11 Apr 2023, 3:42 p.m. | Last Modified: 11 Apr 2023, 5:05 p.m.

Panel Version: 5.24

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071

Publications

Created: 11 Apr 2023, 3:42 p.m.
Last Modified: 11 Apr 2023, 5:11 p.m.
Panel version: 5.19

Tracy Lester (Genetics laboratory, Oxford UK)

I don't know

El Hayek et al (2020) PMID:33350388: We utilized a forward genetics approach to rapidly identify new mutations causing ASD-related behaviors in mice. We screened mice bearing N-ethyl-N-nitrosourea (ENU)-induced mutations (Wang et al., 2015) for defects in ultrasonic vocalizations (USVs) and nest-building behavior. Automated meiotic mapping implicated Kdm5a as a candidate ASD gene and a nonsense mutation at that locus segregated with defective USVs and nest building. In addition to these phenotypes, targeted knockout of Kdm5a resulted in repetitive behaviors, deficits in social interaction, learning, and memory, and abnormal neuronal morphology. KDM5A encodes a chromatin regulator that belongs to the KDM5 family of lysine-specific histone H3 demethylases. Histone H3 lysine 4 trimethyl (H3K4me3) marks are present at gene promoters and active enhancers, and are regulated by multiple factors, including the KDM5 family members KDM5B and KDM5C (Shen et al., 2017). Mutations in lysine demethylases that regulate the demethylation of the H3K4me3 marks have been strongly linked to a host of neurodevelopmental disorders. Finally, we identified nine patients with ASD and lack of speech who have pathogenic KDM5A variants.

7 families were reported, 3 consanguineous with hom del ex6-9, c.2541+1G>T, F477V. and 4 isolated cases - 3 het de novo (p.M1?, R1428L, R1350*) and 1 with AR del ex1-10

Might be sufficient evidence to upgrade this gene to green for both AR and AD ID?
Created: 28 Mar 2023, 1:45 p.m. | Last Modified: 28 Mar 2023, 1:45 p.m.

Panel Version: 5.11

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
ASD, lack of speech

Publications

33350388

Created: 28 Mar 2023, 1:45 p.m.
Last Modified: 28 Mar 2023, 1:45 p.m.
Panel version: 5.11

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
AUTOSOMAL RECESSIVE MENTAL RETARDATION

Publications

21937992

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Olivia Niblock (Genomics England Curator)

Red List (low evidence)

Should be grey. ]No evidence to suggest that variants in this gene are linked to Intellectual Disability. However, there is some evidence linking fusion variants in this gene to poor prognosis in megakaryoblastic leukaemia
Created: 31 Oct 2017, 10:36 a.m.

Mode of inheritance
Unknown

Created: 31 Oct 2017, 10:36 a.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.6

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:05 a.m.

Panel version: 0.306

Details

Mode of Inheritance

BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Sources

Expert Review Green
NHS GMS

Phenotypes

autism spectrum disorder, MONDO:0005258
intellectual disability, MONDO:0001071
El Hayek-Chahrour neurodevelopmental syndrome, OMIM:620820

OMIM

180202

Clinvar variants

Variants in KDM5A

Penetrance

Complete

Publications

Panels with this gene

History Filter Activity

9 May 2024, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: KDM5A were changed from autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071; El Hayek-Chahrour neurodevelopmental syndrome, OMIM:620820

9 May 2024, Gel status: 3

Removed Tag

Eleanor Williams (Genomics England Curator)

Tag gene-checked was removed from gene: KDM5A.

16 Oct 2023, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag gene-checked tag was added to gene: KDM5A.

11 Oct 2023, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: KDM5A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071

11 Oct 2023, Gel status: 3

Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_23_promote_green was removed from gene: KDM5A. Tag Q2_23_NHS_review was removed from gene: KDM5A.

11 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to KDM5A. Source Expert Review Green was added to KDM5A. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

11 Apr 2023, Gel status: 2