Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Autosomal recessive spinocerebellar ataxia type 18 (SCAR18) is an early-onset neurodegenerative disorder caused by biallelic loss-of-function variants in the Glutamate Receptor, Ionotropic, Delta-2 (GRID2) gene. GRID2 encodes the GluD2 subunit of an orphan ionotropic glutamate receptor selectively expressed in cerebellar Purkinje cells, where it is critical for synapse formation and neuronal survival. Patients present with congenital or infantile onset cerebellar atrophy, progressive ataxia and dysarthria. Genetic testing of GRID2 is essential for diagnosis and family counseling.
Genetic evidence supporting the GRID2–SCAR18 association includes four unrelated families and seven affected individuals. A consanguineous pedigree with retinal dystrophy harbored a homozygous exon 2 deletion (p.Gly30_Glu81del) (PMID:25122145); an Italian patient was compound heterozygous for a maternal nonsense variant and a de novo microdeletion (PMID:32387255); and two siblings from another family carried a homozygous exon 14 duplication (PMID:32170608). These probands exhibit classic cerebellar features, and segregation in sibships confirms autosomal recessive transmission.
Across these families, seven probands (including three siblings in one pedigree and two siblings in another) have confirmed biallelic GRID2 variants; three additional affected relatives share genotype–phenotype concordance. Variant classes encompass nonsense, multi-exon deletion, and exon duplication events, all predicted to abolish GluD2 function. c.1954C>A (p.Leu652Ile) serves as an illustrative GRID2 missense change in functional studies of receptor stability (PMID:39312122).
Functional assays in mouse models demonstrate that loss of GRID2 function recapitulates human SCAR18 pathology. Spontaneous hotfoot alleles delete N-terminal domains, causing GluD2 retention in the endoplasmic reticulum and Purkinje cell atrophy (PMID:12752376). The ts3 mouse line with a large Grid2 deletion shows early cerebellar atrophy, defective parallel fiber–Purkinje cell synapses and progressive ataxia (PMID:25250835). These data establish loss-of-function as the primary mechanism.
No studies have refuted the biallelic GRID2 association with SCAR18, though emerging monoallelic variants in GRID2 present distinct dominant-negative phenotypes. Overall, the convergence of multiple independent pedigrees, segregation data, and concordant animal models provides strong clinical validity. Further screening for GRID2 CNVs and truncating alleles is warranted in unexplained early-onset ataxia.
Key Take-Home: GRID2 loss-of-function variants cause autosomal recessive spinocerebellar ataxia 18 with childhood onset cerebellar atrophy and ataxia; GRID2 genetic testing should include sequencing and copy-number analysis to guide diagnosis and management.
Gene–Disease AssociationStrongSeven probands from four unrelated families including two consanguineous pedigrees with multi-generational segregation; concordant loss-of-function data Genetic EvidenceStrong7 probands with biallelic GRID2 variants across four families; nonsense, CNV and deletion alleles segregate in AR fashion Functional EvidenceModerateHotfoot and ts3 mouse models demonstrate GRID2 loss-of-function leading to Purkinje cell degeneration and ataxia |