Ataxia and cerebellar anomalies - narrow panel

Gene: PRRT2

Green List (high evidence)

Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.

Created: 27 Jul 2026, 2:33 p.m. | Last Modified: 27 Jul 2026, 2:33 p.m.

Panel Version: 9.13

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.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, 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).

Created: 27 Jul 2026, 2:29 p.m. | Last Modified: 27 Jul 2026, 2:29 p.m.

Panel Version: 9.12

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066; PRRT2-associated paroxysmal movement disorder, MONDO:0100556

Publications

• 23126439
• 25595153
• 31193310
• 36247910
• 38316952