Zhongbo Chen MRCP, PhD, Pilar Alvarez Jerez MSc, Claire Anderson PhD, Martin Paucar MD, PhD, Jasmaine Lee MSc, Daniel Nilsson PhD, Hannah Macpherson MSc, Annarita Scardamaglia BSc, Kylie Montgomery BSc, John Hardy FMedSci, PhD, Andrew B. Singleton PhD, Arianna Tucci MD, PhD, Katherine D. Mathews MD, PhD, Ying-Hui Fu PhD, Martin Engvall MD, PhD, José Laffita-Mesa MD, PhD, Inger Nennesmo MD, PhD, Anna Wedell MD, PhD, Louis J. Ptáček MD, PhD, Cornelis Blauwendraat PhD, Emil K. Gustavsson PhD, Per Svenningsson MD, PhD, Mina Ryten MD, PhD, Henry Houlden MD, PhD
The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder
Background
The identification of a heterozygous exonic GGC repeat expansion in ZFHX3 underlying spinocerebellar ataxia type 4 (SCA4) has solved a 25-year diagnostic conundrum. We used adaptive long-read sequencing to decipher the pathogenic expansion in the index Utah family and an unrelated family from Iowa of Swedish ancestry. Contemporaneous to our discovery, other groups identified the same repeat expansion in affected individuals from Utah, Sweden, and Germany, highlighting the current pivotal time for detection of novel repeat expansion disorders.
Methods
Given that the pathogenic repeat expansion is rare on a population level, we proposed a common ancestor across all families. Here, we employed targeted long-read sequencing through adaptive sampling, enriching for the chr16q22 region of interest.
Results
Using phased sequencing results from individuals from Utah, Iowa, and Southern Sweden, we confirmed a common ~2000-year-old ancestral haplotype harbouring the repeat expansion.
期刊介绍:
Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.