WWOX – Autosomal Recessive Spinocerebellar Ataxia 12

Autosomal recessive spinocerebellar ataxia 12 (SCAR12) is characterized by progressive cerebellar dysfunction, often with early gait ataxia and variable developmental delay. Biallelic variants in WWOX (HGNC:12799) underlie SCAR12, with initial reports of homozygous null or hypomorphic alleles in multiple families ([PMID:25411445]). The inheritance is autosomal recessive, supported by segregation of WWOX variants in at least two consanguineous pedigrees and confirmation of biallelic changes in affected individuals.

Genetic evidence includes eight affected individuals in two families with homozygous or compound heterozygous WWOX lesions causing SCAR12, plus six additional SCAR12 patients in an independent cohort, totaling 14 individuals with biallelic WWOX variants ([PMID:33916893]). Variant spectrum comprises loss-of-function alleles (nonsense, frameshift, splice site, multi-exon deletions) and hypomorphic missense changes; one recurrent hypomorphic allele is c.140C>G (p.Pro47Arg). Segregation analysis demonstrated co-segregation of WWOX variants with disease in all informative families.

ClinGen genetic curation assigns a Strong level of genetic evidence: multiple unrelated families, bi-allelic WWOX variants in 14 probands, and segregation in two pedigrees. Functional correlation is shown by genotype-phenotype studies: individuals with two predicted null alleles manifest severe early‐onset encephalopathy, whereas hypomorphic allele homozygotes exhibit the milder cerebellar ataxia phenotype of SCAR12.

Mechanism of pathogenicity is consistent with partial loss of WWOX function (haploinsufficiency) for SCAR12; hypomorphic missense alleles retain residual activity, correlating with later‐onset ataxic features. While no dedicated animal models of SCAR12 have been reported, the genotype-phenotype correlation across null and missense alleles provides moderate experimental support.

No conflicting reports have challenged the WWOX–SCAR12 link. Additional rare variants continue to emerge but do not exceed the threshold for further ClinGen scoring.

Key Take-home: Biallelic WWOX variants cause autosomal recessive spinocerebellar ataxia 12 via partial loss of oxidoreductase function, warranting WWOX sequencing in early‐onset ataxia.

References

• Unspecified Journal • 2014 • Homozygous mutations in WWOX in spinocerebellar ataxia 12 and epileptic encephalopathy PMID:25411445
• Cells • 2021 • Neurological Disorders Associated with WWOX Germline Mutations-A Comprehensive Overview. PMID:33916893

Evidence Based Scoring (AI generated)