Large-scale genetic profiling of hereditary ataxias in China: implications for a stepwise molecular diagnostic...

Hereditary ataxias are clinically and genetically heterogeneous, which complicates clinical management, genetic counseling, and scientific research. Efficient molecular diagnosis is essential but requires molecular epidemiological considerations due to the variable genetic landscapes across regions and populations. In China, despite the established predominance of spinocerebellar ataxia type 3 (SCA3), comprehensive data on the genetic landscape of hereditary ataxias are limited and increasingly outdated, leaving insufficient evidence to support an epidemiology-informed molecular diagnostic strategy and its clinical implementation as a diagnostic algorithm.

We retrospectively established a large, real-world, comprehensive cohort of hereditary ataxias (the HARMONY cohort) recruited from two medical centers in the Yangtze River Delta region of China (2008-2024) for genetic profiling. Molecular diagnoses were categorized into four classifications ('Definitive', 'Probable', 'Unclear', 'Undiagnosed') by integrating previously identified causative variants with results from systematic genetic testing in etiologically undetermined probands, and the associated variants were mapped onto genetic landscapes.

A total of 2096 probands were included in the HARMONY cohort, achieving a molecular diagnostic yield of 84.9%, with 1715 (81.8%) 'Definitive' and 65 (3.1%) 'Probable' positive diagnoses, alongside 87 (4.2%) 'Unclear' and 229 (10.9%) 'Undiagnosed' cases. While the genetic landscape was dominated by variants underlying SCA3 (1249; 59.6%), with SCA2 (150; 7.2%), SCA1 (139; 6.6%), SCA6 (51; 2.4%), putative SCA36 (36; 1.7%), and SCA12 (35; 1.7%) constituting the major subtypes, the genetic profiling revealed a long tail of rare genotypes. Onset age distributions were characterized for genotypes with ≥ 5 probands. No probands were found to carry expansions in ZFHX3, BEAN1, DAB1, THAP11, or FXN.

Genetic profiling of the HARMONY cohort revealed a skewed genetic landscape dominated by a few common repeat-expansion subtypes, alongside a markedly heterogeneous long tail of rare etiologies. The holistic profile supports a stepwise molecular diagnostic strategy, under which we propose a YRD (Yangtze River Delta)-oriented candidate diagnostic algorithm. This study provides an evidence base for early molecular diagnosis, prioritization of therapeutic development, and adaptive design of diagnostic tools for hereditary ataxias.