Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions.

Purpose of review: Autosomal dominant cerebellar ataxias, also known as spinocerebellar ataxias (SCAs), are genetically and clinically diverse neurodegenerative disorders characterized by progressive cerebellar dysfunction. Despite advances in sequencing technologies, a large proportion of patients with SCA still lack a definitive genetic diagnosis. The advent of advanced bioinformatic tools and emerging genomics technologies, such as long-read sequencing, offers an unparalleled opportunity to close the diagnostic gap for hereditary ataxias. This article reviews the recently identified repeat expansion SCAs and describes their molecular basis, epidemiology, and clinical features.

Recent findings: Leveraging advanced bioinformatic tools and long-read sequencing, recent studies have identified novel pathogenic short tandem repeat expansions in FGF14, ZFHX3, and THAP11, associated with SCA27B, SCA4, and SCA51, respectively. SCA27B, caused by an intronic (GAA)•(TTC) repeat expansion, has emerged as one of the most common forms of adult-onset hereditary ataxias, especially in European populations. The coding GGC repeat expansion in ZFHX3 causing SCA4 was identified more than 25 years after the disorder's initial clinical description and appears to be a rare cause of ataxia outside northern Europe. SCA51, caused by a coding CAG repeat expansion, is overall rare and has been described in a small number of patients. The recent identification of three novel pathogenic repeat expansions underscores the importance of this class of genomic variation in the pathogenesis of SCAs. Progress in sequencing technologies holds promise for closing the diagnostic gap in SCAs and guiding the development of therapeutic strategies for ataxia.