importance of functional analysis: a cautionary case of cerebellar ataxia

Introduction. Cerebellar ataxias are a heterogeneous group of disorders with various cerebellar and extracerebellar manifestations. The underlying aetiology in early-onset, progressive, sporadic ataxia, is often autosomal recessive cerebellar ataxia (ARCA). The advent and rapid clinical integration of next-generation sequencing (NGS) has made it increasingly possible to provide a genetic diagnosis for patients with suspected ARCA. However, one of the greatest challenges of NGS is the interpretation and reclassification of variants of uncertain significance (VUS). Case report. Ataxia telangiectasia was suspected due to progressive teenage-onset ataxia in a 42-year-old woman with a history of breast cancer, ovarian mass, and elevated alpha-fetoprotein and CA-125. ATM sequencing demonstrated a homozygous missense VUS. However, functional studies clarified that this VUS was not pathogenic, but there was reduction in senataxin. This enabled clarification that the diagnosis was ataxia with oculomotor apraxia type 2. Conclusion. Our case highlights the importance of functional studies, where possible, to enable reclassification of VUSs.