An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches

Abstract

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield.

Bridging the gap: a prospective trial comparing programmable targeted long-read sequencing and short-read genome sequencing for genetic diagnosis of cerebellar ataxia

“…In addition, nine clinically suspicious variants were identified as likely candidates (VUS), requiring future clinical followup and functional studies to confirm pathogenicity. Overall clinically relevant small variants were found in 15% of cases, consistent with literature on their contribution to CA (Rudaks et al 2024). Notably, all of these variants affected protein coding or nearby flanking sequences and therefore are detectable by standard exome sequencing.…”

“…In addition to RE, a variety of other pathogenic variants can cause CA (Beaudin et al 2019;Rudaks et al 2024). Therefore, we analyzed the SR-GS data for SNV/indel, CNV and mitochondrial DNA (mtDNA) variants.…”

“…There are approximately 100 clinically recognized CA, with similar numbers caused by autosomal dominant and autosomal recessive mechanisms. The prevalence of these disorders varies widely depending on genetic ancestry and geographical location, with estimates of a global average of ~6:100,000 (Ruano et al 2014;Rudaks et al 2024). These debilitating disorders predominantly impact locomotion, hand coordination, speech, swallowing and vision.…”

“…Non-RE pathogenic variants in ~100 other genes also contribute to disease prevalence (Beaudin et al 2019;Rudaks et al 2024), presenting a daunting panel of unusual variants and genes requiring examination. Diagnostic testing methodologies and outcomes for CA vary broadly.…”