Ataxia and cerebellar anomalies - narrow panel

Gene: GPN2

Red List (low evidence)

Smith et al. 2026 (PMID 42392036) investigated a Perrault syndrome cohort via exome sequencing.
Family F2 comprised two affected sisters with bilateral profound sensorineural hearing loss (SNHL), primary ovarian insufficiency (POI), and cerebellar ataxia. Brain MRI revealed cerebellar atrophy in both. Both were homozygous for GPN2 c.664A>G p.Asn222Asp.
Family F3 comprised a single affected proband presenting with profound SNHL, primary amenorrhea, and mild intellectual disability, also homozygous for GPN2 c.664A>G p.Asn222Asp. Cerebellar atrophy was noted on brain MRI. N.B. Haplotype analysis in the affected members of families F2 and F3 revealed a shared homozygous region of 662 kb encompassing the GPN2 locus, indicative of a shared ancestor.
Age at onset for affected probands is unknown, however age at last examination was in the 2nd or 3rd decade (supplemental data), suggesting early onset.
Before this study, no Mendelian disease had been attributed to GPN2 or its paralogs, GPN1 and GPN3; no animal model exists supporting pathogenicity or delineating the potential mechanism.

Conclusion: A single variant with potential founder effect is implicated in ataxia (n= 2 probands from 1 family)/ cerebellar atrophy (n=3 probands from 2 families); age of onset for the probands cited is unknown.
Suggest red rating (low evidence).
Sources: Literature

Created: 28 Jul 2026, 4:38 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebellar ataxia (MONDO:0000437)

Publications

• 42392036