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27 Jul 2026	Intellectual disability v10.69	PRRT2	Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 31193310 El Achkar et al., 2019 Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, not cognitive impairment. PMID: 25595153 Delcourt et al., 2015 Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026).; to: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the splice variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 31193310 El Achkar et al., 2019 Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, no cognitive impairment seen in the proband. PMID: 25595153 Delcourt et al., 2015 Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases. PMID: 23126439 Labate et al., 2012 Homozygous c.649dupC mutation in PRRT2 detected in 2 sibs from a consanguineous Italian family resulted in ID, episodic ataxia, and absences. 4 other affected family members, het for the same mutation, presented only with benign familial infantile seizures / familial paroxysmal kinesigenic dystonia. DOI: 10.1055/s-0045-1810051 Eshrif & Adofani, 2025 Case report of a family with epilepsy and dyskinesia due to a homozygous PRRT2 variant c.649dup, p.(Arg217Profs8). 3 sibs affected, all 3 presented with focal seizures at 3-8 months old, and 2/3 individuals also had dyskinesia. Family history not discussed, parents assumed to be unaffected from the pedigree. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026).
27 Jul 2026	Intellectual disability v10.69	PRRT2	Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 25595153 Delcourt et al., 2015 https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.; to: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 31193310 El Achkar et al., 2019 Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs*8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, not cognitive impairment. PMID: 25595153 Delcourt et al., 2015 Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026).
30 Jan 2023	Intellectual disability v4.53	CHKA	Arina Puzriakova Tag Q3_22_rating was removed from gene: CHKA.
30 Jan 2023	Intellectual disability v4.53	CHKA	Arina Puzriakova reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
30 Jan 2023	Intellectual disability v4.52	CHKA	Arina Puzriakova 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	Intellectual disability v3.1742	CHKA	Eleanor Williams commented on gene: CHKA
11 Oct 2022	Intellectual disability v3.1742	CHKA	Eleanor Williams Tag Q3_22_MOI was removed from gene: CHKA.
23 Aug 2022	Intellectual disability v3.1679	CHKA	Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA. Tag Q3_22_MOI tag was added to gene: CHKA.
23 Aug 2022	Intellectual disability v3.1679	CHKA	Sarah Leigh edited their review of gene: CHKA: Added comment: 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.; Changed rating: GREEN
23 Aug 2022	Intellectual disability v3.1679	CHKA	Sarah Leigh Classified gene: CHKA as Amber List (moderate evidence)
23 Aug 2022	Intellectual disability v3.1679	CHKA	Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
23 Aug 2022	Intellectual disability v3.1679	CHKA	Sarah Leigh Gene: chka has been classified as Amber List (Moderate Evidence).
25 Feb 2022	Intellectual disability v3.1500	CHKA	Konstantinos Varvagiannis 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 Added comment: 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