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Intellectual disability

Gene: CHKA

Green List (high evidence)
CHKA (choline kinase alpha)
EnsemblGeneIds (GRCh38): ENSG00000110721
EnsemblGeneIds (GRCh37): ENSG00000110721
OMIM: 118491, Gene2Phenotype
CHKA is in 4 panels

4 reviews

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 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Eleanor Williams (Genomics England Curator)

Removed the Q3_22_MOI rating tag, this gene was on the last signed off panel (although grey).
Created: 11 Oct 2022, 1:23 p.m. | Last Modified: 11 Oct 2022, 1:23 p.m.
Panel Version: 3.1742
Created: 11 Oct 2022, 1:23 p.m.
Last Modified: 11 Oct 2022, 1:23 p.m.
Panel version: 3.1742

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35202461 reports five CHKA variants in five unrelated cases with a neurodevelopmental disorder, which includes intellectual disability, epileptic
encephalopathy and severe microcephaly (PMID: 35202461). Suportive functional studies are also presented in this article.
Created: 23 Aug 2022, 1 p.m. | Last Modified: 23 Aug 2022, 1 p.m.
Panel Version: 3.1679
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 23 Aug 2022, 12:45 p.m. | Last Modified: 23 Aug 2022, 12:45 p.m.
Panel Version: 3.1679
Created: 23 Aug 2022, 12:45 p.m.
Last Modified: 23 Aug 2022, 12:45 p.m.
Panel version: 3.1679

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants.

Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6.

Eventual previous genetic testing was not discussed.

Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies.

Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype.

3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2):
- c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families],
- c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents],
- c.2T>C/p.(Met1?) [1 hmz individual born to related parents],
- c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual.

CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes.

CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP.

As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants].

Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc.

CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect.

In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine).

Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively).

NMD is thought to underly the deleterious effect of the frameshift one (not studied).

The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein.

Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714).

There is no associated phenotype in OMIM, Gene2Phenotype or SysID.

Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset).
Sources: Literature
Created: 25 Feb 2022, 2:35 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature

Publications

Created: 25 Feb 2022, 2:35 p.m.

Panel version: 3.1500

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Abnormal muscle tone
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Microcephaly
  • Abnormality of movement
  • Abnormality of nervous system morphology
  • Short stature
OMIM
118491
Clinvar variants
Variants in CHKA
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: CHKA.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

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

11 Oct 2022, Gel status: 2

Removed Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_22_MOI was removed from gene: CHKA.

23 Aug 2022, Gel status: 2

Added Tag, Added Tag

Sarah Leigh (Genomics England Curator)

Tag Q3_22_rating tag was added to gene: CHKA. Tag Q3_22_MOI tag was added to gene: CHKA.

23 Aug 2022, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: chka has been classified as Amber List (Moderate Evidence).

25 Feb 2022, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: CHKA was added gene: CHKA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHKA were set to 35202461 Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature Penetrance for gene: CHKA were set to Complete Review for gene: CHKA was set to GREEN