Yield of Whole-Exome Sequencing in Children With Nonacquired Chronic Ataxia: A Prospective Study From a Single Tertiary Care Hospital in South India.

BACKGROUND

Chronic childhood ataxia presents a diagnostic challenge as multiple conditions (congenital, acquired, and genetic) in pediatric neurology present with chronic ataxia. Overlapping phenotypes, developmental variability, and limited availability of specialized testing complicate diagnosis. Around 50-70% cases remain undiagnosed with traditional approaches. While acute ataxias frequently result from acquired etiologies such as infection or toxicity, chronic and progressive cerebellar ataxia cases are predominantly genetic in etiology. In recent years, wide availability and reduced costs have led to increasing use of whole-exome sequencing (WES) in pediatric neurology. Studies on the etiology of chronic childhood ataxia using genetic tests, especially WES, are sparse and mainly from developed countries. We conducted this study in a single tertiary care hospital in South India to evaluate the diagnostic yield of WES and etiological spectrum in children with nonacquired chronic ataxia.

METHODS

A hospital-based prospective cohort study of children (≤18 years) with chronic ataxia (persisting for more than 6 months) was designed. Comprehensive clinical evaluation, including family history, assessment of severity using the Scale for the Assessment and Rating of Ataxia score, magnetic resonance imaging with advanced sequences (diffusion weighted imaging, susceptibility weighted imaging), and biochemical investigations when indicated, was performed in all children. After acquired causes were ruled out, WES was performed at 80×-100×coverage depth in all eligible children. The genetic variants were classified according to the American College of Medical Genetics guidelines. Statistical analysis of the results was performed using SPSS (version 30).

RESULTS

Eighty-three children met the study criteria, and the cohort had early-onset disease (mean age 3.6 ± 3.0 years). There was 81.9% consanguinity. WES identified the cause of ataxia in 74/83 (89.1%) with pathogenic/likely pathogenic variants. It identified variants in 45 distinct disease-causing genes. ATM mutations predominated (19.3%), followed by APTX (7.2%), CLN6 (3.6%), and EPM2A (3.6%).

CONCLUSIONS

WES showed a high diagnostic yield. This study supports WES as a good diagnostic strategy for childhood chronic ataxias, particularly in populations with higher rates of consanguinity. The early diagnoses based on genetic testing would help in providing families with prognostic information, surveillance, genetic counseling, and avoidance of additional diagnostic testing. It may help in targeted therapeutic interventions in few cases.