Childhood‐Onset Cerebellar Ataxia from Homozygous XRCC1 c. 1293G >C Variant

Defects in single-strand DNA break repair (SSBR) are increasingly recognized as a cause of hereditary cerebellar ataxia, linking genome maintenance to cerebellar integrity.1, 2 Among these, biallelic XRCC1 variants have been described in only a few patients with variable combinations of ataxia, oculomotor apraxia, and axonal neuropathy.3, 4 We report a child with early-onset ataxia associated with a homozygous XRCC1 missense variant, further delineating the phenotypic spectrum and reinforcing XRCC1 as a bona fide recessive ataxia gene. The proband, a 4-year-old male of Indian ancestry, was born to non-consanguineous parents after an uncomplicated pregnancy and delivery. Early motor development was delayed (sitting at 8 months, walking at 17 months) with early axial instability and frequent falls. Cognitive and language milestones were age-appropriate. Family history was negative for neurologic disease. Neurologic examination revealed striking axial and appendicular cerebellar ataxia (Video 1, part 1). Gait was broad-based with truncal sway (Video 1, part 2); dysmetria and dysdiadochokinesis were present, but there was no oculomotor apraxia or nystagmus. Deep tendon reflexes were present yet diffusely reduced. The Scale for the Assessment and Rating of Ataxia (SARA) score was 17.5. Brain MRI at age 3 years showed no cerebellar atrophy. Trio exome sequencing identified a homozygous likely pathogenic variant in XRCC1: NM_006297.3:c.1293G>C p.(Lys431Asn). Both parents were heterozygous carriers. XRCC1 encodes X-ray repair cross-complementing protein 1, a scaffold protein coordinating base excision and single-strand break repair through interaction with DNA ligase III, PARP1, and polynucleotide kinase phosphatase.3, 5 Notably, c.1293G>C is a missense variant that simultaneously affects splicing. Multiple splice prediction algorithms indicate loss of the exon 11 donor site, and functional studies by Hoch et al demonstrated aberrant transcript retention and reduced XRCC1 mRNA and protein levels in patient-derived fibroblasts carrying this allele in trans with a truncating variant.3, 6 A limitation of our report is the lack of patient-derived RNA analysis, which would have allowed direct confirmation of the splicing defect and assessment of residual transcript levels in the homozygous state of the variant. This variant has been previously reported in three individuals of South Asian ancestry: An adult of East Indian descent with oculomotor apraxia, progressive ataxia, sensorimotor axonal neuropathy, and cerebellar atrophy and two unrelated patients of Pakistani origin with onset at age three, slowly progressive gait ataxia, and sensorimotor neuropathy but only mild ocular abnormalities. One of the reported patients had a dual diagnosis involving CLCN1. Homozygosity mapping revealed a shared haplotype on chromosome 19, supporting a founder effect in South Asian populations.3, 4 Our patient demonstrates an even earlier onset (