Ataxia and cerebellar anomalies - narrow panel

Gene: GRID2

Evidence for biallelic variants causing ataxia come from
PMID: 23611888 - Utine et al 2013 - homozygous partial deletion of GRID2 in 3 children (symptom onset <5 years of age) in one large consanguineous Turkish family. Deletions were identified in by SNP arrays.

PMID: 24078737 - Hills et al 2013 - 2 families with cerebellar ataxia, eye movement abnormalities, and global developmental delay. 1 extended family of Jordanian ancestry with 3 affected children, with homozygous deletions in GRID2 identified by aCGH. 1 family of Mexican ancestry and 1 affected child with compound het deletions in GRID2 (1 inherited from mother, other appears de novo).

Created: 22 Jan 2026, 6:48 p.m. | Last Modified: 22 Jan 2026, 6:48 p.m.

Panel Version: 8.50

Publications

• 23611888
• 24078737

Green List (high evidence)

Comment on list classification: While most reported GRID2-related SCA cases show autosomal recessive inheritance, there are 3 unrelated pedigrees described with missense variants in GRID2 M3S2 pore domain, causing dominant / semidominant cerebellar ataxia. One childhood onset case was reported, with a homozygous missense variant in the M3 domain. The heterozygous individuals had first ataxia symptoms in adulthood, which is not in the scope of this panel. Hence, GRID2 should remain Green with a BIALLELIC mode of inheritance, until more evidence emerges.

Created: 16 Jan 2026, 12:07 p.m. | Last Modified: 16 Jan 2026, 12:07 p.m.

Panel Version: 8.46

PMID: 25841024 Coutelier et al., 2015
Large Algerian family with a dominant GRID2 mutation, segregating with adult-onset, paucisymptomatic, slowly progressive, cerebellar ataxia in 7 adults and congenital ataxia in 1 child that was homozygous for the variant: GRID2 c.1966C>G/p.Leu656Val.
Also screened an additional ataxia cohort and identified 2 missense de novo GRID2 mutations in 2 children: c.1960G>A, p.Ala654Thr and c.1961C>A, p.Ala654Asp. None of the 3 missense mutations were reported in gnomAD.

PMID: 35882834 Koh et al., 2022
Report of a Japanese dominant cerebellar ataxia family with a heterozygous GRID2 mutation - mother and her 3 children affected; age of onset ranged from 30s to 50s. Symptoms at onset were gait disturbance and/or dysarthria; patients exhibited truncal and limb ataxia without eye movement disorders, pyramidal tract signs, or sensory disturbance. No cognitive impairment or hearing loss. All affected individuals carried GRID2 NM_001510.4: c.1966C>G, p.Leu656Val - method: WES. MRI showed cerebellar atrophy in 2 patients (others not screened).

PMID: 37944084 Allen et al., 2023
Review of 70 reported GRID2 missense variants (3 this study, 5 published, 62 ClinVar).
Patient with a de novo heterozygous GRID2 c.1945A>G p.Thr649Ala variant; presented with cerebellar ataxia, dysarthria, strabismus, and significant cerebellar volume loss on MRI. Variant also in the M3 domain.

Functional evidence: lurcher mouse carrying p.Ala654(+/-) in Grid2 exhibits degeneration of cerebellar Purkinje cells and ataxic gait (PMID: 9285588 Zuo et al., 1997). Transgenic mice with Grid2 knockout (the hotfoot strain) exhibit ataxia, impaired locomotion, and Purkinje cell abnormalities (PMID: 21460832 Kakegawa et al., 2012).

GRID2 is associated with Spinocerebellar ataxia, autosomal recessive 18, MIM: 616204. Gene2Phenotype lists a Strong association between GRID2 and both mono- and bi-allelic cerebellar ataxia. Resources accessed 16th Jan 2025.

Created: 16 Jan 2026, 12:01 p.m. | Last Modified: 16 Jan 2026, 12:01 p.m.

Panel Version: 8.46

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Progressive cerebellar ataxia, HP:0002073

Publications

• 9285588
• 21460832
• 25841024
• 35882834
• 37944084

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments