Journal article
Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4
Movement disorders, Vol.39(3), pp.486-497
03/2024
DOI: 10.1002/mds.29704
PMID: 38197134
Abstract
Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive.
Inspired by pathogenic structural variation implicated in other 16q-ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region.
We adopted a targeted long-read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features.
Using this approach, we found a heterozygous (GGC)
repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short-read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in-house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare.
These findings support the utility of adaptive long-read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Details
- Title: Subtitle
- Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4
- Creators
- Zhongbo Chen - University College LondonEmil K Gustavsson - University College LondonHannah Macpherson - University College LondonClaire Anderson - University College LondonChris Clarkson - Queen Mary University of LondonClarissa Rocca - University College LondonEleanor Self - University College LondonPilar Alvarez Jerez - National Institute of Neurological Disorders and StrokeAnnarita Scardamaglia - University College LondonDavid Pellerin - University College LondonKylie Montgomery - University College LondonJasmaine Lee - University College LondonDelia Gagliardi - University College LondonHuihui Luo - University College LondonJohn Hardy - Hong Kong University of Science and TechnologyJames Polke - National Hospital for Neurology and NeurosurgeryAndrew B Singleton - National Institute on AgingCornelis Blauwendraat - National Institute on AgingKatherine D Mathews - University of IowaArianna Tucci - Queen Mary University of LondonYing-Hui Fu - University of California, San FranciscoHenry Houlden - National Hospital for Neurology and NeurosurgeryMina Ryten - University College LondonLouis J Ptáček - University of California, San FranciscoGenomics England Research Consortium
- Resource Type
- Journal article
- Publication Details
- Movement disorders, Vol.39(3), pp.486-497
- DOI
- 10.1002/mds.29704
- PMID
- 38197134
- NLM abbreviation
- Mov Disord
- eISSN
- 1531-8257
- Grant note
- Leonard Wolfson Foundation MRC
- Language
- English
- Electronic publication date
- 01/10/2024
- Date published
- 03/2024
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984544956702771
Metrics
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