The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder

Zhongbo Chen; Pilar Alvarez Jerez; Claire Anderson; Martin Paucar; Jasmaine Lee; Daniel Nilsson; Hannah Macpherson; Annarita Scardamaglia; Kylie Montgomery; John Hardy; Andrew B Singleton; Arianna Tucci; Katherine D Mathews; Ying-Hui Fu; Martin Engvall; José Laffita-Mesa; Inger Nennesmo; Anna Wedell; Louis J Ptáček; Cornelis Blauwendraat; Emil K Gustavsson; Per Svenningsson; Mina Ryten; Henry Houlden

doi:10.1002/mds.30077

Back

The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder

Journal article

Open access

Peer reviewed

The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder

Zhongbo Chen, Pilar Alvarez Jerez, Claire Anderson, Martin Paucar, Jasmaine Lee, Daniel Nilsson, Hannah Macpherson, Annarita Scardamaglia, Kylie Montgomery, John Hardy, …

Movement disorders, Vol.40(2), pp.363-369

02/2025

DOI: 10.1002/mds.30077

PMCID: PMC11832790

PMID: 39635987

Files and links (1)

url

https://doi.org/10.1002/mds.30077View

Published (Version of record) Open Access

Abstract

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. 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. 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. This 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.

Ataxia

haplotype

spinocerebellar ataxia type 4

repeat expansion disorder

long‐read sequencing

Details

Title: Subtitle: The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder
Creators: Zhongbo Chen - University College London
Pilar Alvarez Jerez - University College London
Claire Anderson - University College London
Martin Paucar - Karolinska University Hospital
Jasmaine Lee - University College London
Daniel Nilsson - Karolinska University Hospital
Hannah Macpherson - University College London
Annarita Scardamaglia - University College London
Kylie Montgomery - University College London
John Hardy - University College London
Andrew B Singleton - National Institutes of Health
Arianna Tucci - Queen Mary University of London
Katherine D Mathews - University of Iowa
Ying-Hui Fu - University of California, San Francisco
Martin Engvall - Karolinska Institutet
José Laffita-Mesa - Karolinska Institutet
Inger Nennesmo - Karolinska Institutet
Anna Wedell - Karolinska Institutet
Louis J Ptáček - University of Iowa
Cornelis Blauwendraat - National Institute on Aging
Emil K Gustavsson - University College London
Per Svenningsson - Karolinska University Hospital
Mina Ryten - University College London
Henry Houlden - University College London
Resource Type: Journal article
Publication Details: Movement disorders, Vol.40(2), pp.363-369
DOI: 10.1002/mds.30077
PMID: 39635987
PMCID: PMC11832790
NLM abbreviation: Mov Disord
ISSN: 0885-3185
eISSN: 1531-8257
Publisher: Wiley
Grant note: Michael J. Fox Foundation for Parkinson's Research NIH HHS Medical Research Council
Language: English
Electronic publication date: 12/05/2024
Date published: 02/2025
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984757064402771

Metrics

32 Record Views

1 Times Cited - Web of Science