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: NM₀06297. 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 (<1 year) and absent oculomotor findings, extending the phenotypic range to infantile-onset “pure” cerebellar ataxia with likely evolving neuropathic features. The variant is extremely rare in population databases (gnomAD v4. 1. 0, AC: 22, AF: 0. 00001363), observed exclusively in South Asian populations (MAF: 0. 0002416) with one reported homozygote of unknown phenotype. Across these cases, p. Lys431Asn appears as a recurrent, South Asian-founder variant. 3, 4 Its phenotypic variability—from early childhood to adulthood and with or without oculomotor signs—suggests partial functional disruption of XRCC1-ligase III interactions rather than complete loss of SSBR function. In contrast, null alleles might be embryonically lethal, consistent with XRCC1-knockout mouse data showing early lethality and widespread apoptosis. 3, 7 Future functional studies will be essential to elucidate how XRCC1 variants disrupt single-strand break repair and contribute to cerebellar and peripheral nerve vulnerability, as well as to determine whether heterozygous or homozygous carriers may have an increased susceptibility to malignancy. 8, 9 Clinically, XRCC1-associated ataxia should be distinguished from other SSBR-related disorders such as those associated with APTX (AOA1) and PNKP (AOA4), which share overlapping features but more consistently exhibit oculomotor apraxia and cerebellar atrophy. 2, 5 Early recognition of the XRCC1 phenotype—particularly when MRI and ocular findings are not yet present—supports timely genomic testing, anticipatory management, and genetic counseling. In summary, the biallelic variants in XRCC1 cause early childhood-onset cerebellar ataxia. Recognition of this genotype–phenotype correlation facilitates accurate diagnosis within the expanding group of DNA repair-associated ataxias. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript: A. Writing of first draft, B. Review and critique G. R.: 1B, 1C, 3A. M. F.: 1B, 1C, 3B. A. T.: 1B, 1C, 3B. J. R.: 1B, 1C, 3B. E. G.: 2C, 3C. D. E. F.: 1A, 2C, 3B. K. Y.: 1A, 1B, 1C, 3B. We thank the patient and family for their participation and consent. Ethical Compliance Statement: Institutional policies determined that individual case reports do not require IRB review. Written informed consent for publication, including identifiable video material, was obtained from the patient's guardians in accordance with HIPAA and the Declaration of Helsinki. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Financial disclosure related to the research covered in this article. The authors declare no other financial relationships related to the submitted work. Funding Sources and Conflict of Interest: Research in the Ebrahimi-Fakhari Laboratory is supported by the National Institute of Neurological Disorders and Stroke (K08NS123552, 1U54NS148312–01), the Spastic Paraplegia Foundation, the CureAP4 Foundation, the Lilly & Blair Foundation, the CureSPG4 Foundation, the New England Epilepsy Foundation, the Boston Children's Hospital Translational Research Program, and the Boston Children's Hospital TIDO Accelerator Award. MF-S is supported by a fellowship from the Dystonia Medical Research Foundation. The authors declare no conflicts of interest relevant to this article. Financial Disclosures for the previous 12 months: The authors declare no additional disclosures to report. Author disclosures are available in the Supporting Information. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Disclosure. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Ribeiro et al. (Tue,) studied this question.