Objective: To characterize the genetic spectrum and inheritance patterns of hereditary ataxia in a large cohort from Saudi Arabia, a population with a high rate of consanguinity.

Background: Hereditary ataxias are genetically heterogeneous neurodegenerative disorders. Data from highly consanguineous populations remain limited, and understanding their genetic architecture may improve diagnostic strategies and expand the known mutational spectrum.

Method: This retrospective multicenter study included patients with genetically confirmed hereditary ataxia from eight tertiary referral centers in Saudi Arabia. Patients with pathogenic, likely pathogenic, or segregating variants of uncertain significance were included. Genetic testing modalities included whole-exome sequencing, whole-genome sequencing, targeted ataxia panels, and single-gene testing. Patients with incomplete clinical or genetic data were excluded.

Results: Among 1,742 screened individuals, 310 patients were included. The cohort consisted predominantly of pediatric patients (282/310, 91.0%) with near equal sex distribution (48.7% male). Parental consanguinity was present in 95.2% of cases, and a positive family history was reported in 57.5%. Whole-exome sequencing was the most frequently used diagnostic modality (68.1%), followed by ataxia gene panels (22.6%), single-gene testing (11.3%), and whole-genome sequencing (9.0%). Overall, 73.9% of variants were classified as pathogenic or likely pathogenic, while 26.1% were variants of uncertain significance, several appearing novel. The most frequently identified genes were ATM (16.8%), SACS (5.5%), and MRE11 (5.5%). Autosomal recessive inheritance predominated (83.9%), followed by autosomal dominant (10.8%), sporadic (3.8%), and X-linked (1.4%) patterns. Homozygous variants accounted for 76.5% of cases.

Conclusion: This nationwide study represents one of the largest genetically characterized hereditary ataxia cohorts from a highly consanguineous population. Autosomal recessive ataxias predominated, with ATM emerging as the most frequent gene. Several potentially novel variants were identified, expanding the mutational spectrum. Ongoing analyses, including repeat expansion testing, may further refine these findings.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-landscape-of-hereditary-ataxia-in-a-highly-consanguineous-population-a-nationwide-multicenter-study/