The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder.
The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
London, GB · Author affiliation
Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK.Location evidence
Bethesda, US · Author affiliation
Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.Location evidence
Stockholm, SE · Author affiliation
Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.Location evidence
Hong Kong, HK · Author affiliation
Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China.Location evidence
Iowa City, US · Author affiliation
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.Location evidence
San Francisco, US · Author affiliation
Department of Neurology, University of California San Francisco, San Francisco, California, USA.Location evidence
Cambridge, GB · Author affiliation
UK Dementia Research Institute at the University of Cambridge, Cambridge, UK.Location evidence
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Original abstract
BackgroundThe 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.MethodsGiven 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.ResultsUsing phased sequencing results from individuals from Utah, Iowa, and Southern Sweden, we confirmed a common ~2000-year-old ancestral haplotype harbouring the repeat expansion.ConclusionThis study provides further insight into the genetic architecture of SCA4. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.