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

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

Mov Disord. 2024 Dec 5. doi: 10.1002/mds.30077. Online ahead of print.

Authors

Zhongbo Chen^{1

2}, Pilar Alvarez Jerez^{3

4}, Claire Anderson^{5

6}, Martin Paucar^{7

8}, Jasmaine Lee⁹, Daniel Nilsson^{10

11}, Hannah Macpherson^{3

5

6}, Annarita Scardamaglia⁹, Kylie Montgomery^{5

6

9}, John Hardy^{3

12

13

14

15}, Andrew B Singleton^{4

16}, Arianna Tucci¹⁷, Katherine D Mathews^{18

19}, Ying-Hui Fu^{20

21

22

23}, Martin Engvall^{24

25}, José Laffita-Mesa^{8

26}, Inger Nennesmo²⁷, Anna Wedell²⁵, Louis J Ptáček^{19

20

21

22}, Cornelis Blauwendraat^{4

16}, Emil K Gustavsson^{5

6}, Per Svenningsson^{7

8}, Mina Ryten^{5

6

28

29}, Henry Houlden⁹

Affiliations

¹ Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK.
² The Francis Crick Institute, London, UK.
³ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London, UK.
⁴ 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.
⁵ Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, UCL, London, UK.
⁶ NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL, London, UK.
⁷ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁹ Department of Neuromuscular Disease, Queen Square Institute of Neurology, UCL, London, UK.
¹⁰ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
¹¹ Science for Life Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹² Reta Lila Weston Institute, Queen Square Institute of Neurology, UCL, London, UK.
¹³ UK Dementia Research Institute, UCL, London, UK.
¹⁴ NIHR University College London Hospitals Biomedical Research Centre, London, UK.
¹⁵ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China.
¹⁶ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
¹⁷ William Harvey Research Institute, Queen Mary University of London, London, UK.
¹⁸ Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
¹⁹ Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
²⁰ Department of Neurology, University of California San Francisco, San Francisco, California, USA.
²¹ Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
²² Weill Institute for Neuroscience, University of California San Francisco, San Francisco, California, USA.
²³ Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, California, USA.
²⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
²⁵ Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
²⁶ Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
²⁷ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
²⁸ UK Dementia Research Institute at the University of Cambridge, Cambridge, UK.
²⁹ Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

PMID: 39635987
DOI: 10.1002/mds.30077

Abstract

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.

Conclusion: 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.

Keywords: ataxia; haplotype; long‐read sequencing; repeat expansion disorder; spinocerebellar ataxia type 4.

Abstract

Grants and funding