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

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
PMCID: PMC11832790
DOI: 10.1002/mds.30077

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

Zhongbo Chen et al. Mov Disord. 2025 Feb.

. 2025 Feb;40(2):363-369.

doi: 10.1002/mds.30077. Epub 2024 Dec 5.

Authors

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
PMCID: PMC11832790
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.

PubMed Disclaimer

Figures

**FIG. 1**
Characterizing the repeat expansion (RE) haplotype using adaptive sampling‐enabled targeted long‐read sequencing. (A) Six ultra‐rare single nucleotide variants (SNVs) identified by Figueroa et al. were associated with the repeat expansion haplotype in affected individuals from Utah, Iowa, and Sweden. Sizing of the phased structural variants including the GGC repeat expansion used Sniffles. 1 represents presence of a variant, 0 represents absence of the particular variant. | denotes a phased variant. / denotes unphased variant. The first allele contains the repeat expansion (ie, 1|0 shows the presence of the SNV on the repeat‐expansion‐containing allele. It is worth noting that four SNVs chr16:72787719 A>G; chr16:72787737 A>G; chr16:72787739 T>C; and chr16:72787743 A>G) are located within the expanded repeat (B). SNVs in the repeat expansion haplotype (taking Utah1 repeat expansion haplotype as the index haplotype) within 50 kb of the repeat expansion locus (vertical dashed line) showed strong similarities among cases from Utah, Iowa, and Southern Sweden. SNVs matching the index repeat expansion‐haplotype are shown in red. SNVs present that do not match those within the repeat‐containing haplotype are shown in gray. (C). Representative extended phased haplotypes showed a large identical haplotype block (boxed) with crossover events from individuals with spinocerebellar ataxia type 4 from Utah, Iowa, and Sweden. This led us to conclude that the haplotype associated with *ZFHX3* GGC repeat expansion underlying spinocerebellar ataxia type 4 has a common ancestral founder. [Color figure can be viewed at wileyonlinelibrary.com]

See this image and copyright information in PMC

References

1. Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996;59(2):392–399. - PMC - PubMed
1. Chen Z, Gustavsson EK, Macpherson H, Anderson C, Clarkson C, Rocca C, et al. Adaptive long‐read sequencing reveals GGC repeat expansion in ZFHX3 associated with spinocerebellar ataxia type 4. Mov Disord 2024;39(3):486–497. - PubMed
1. Paucar M, Nilsson D, Engvall M, Laffita‐Mesa J, Söderhäll C, Skorpil M, et al. Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs. J Intern Med 2024;296(3):234–248. - PubMed
1. Wallenius J, Kafantari E, Jhaveri E, Gorcenco S, Ameur A, Karremo C, et al. Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: a poly‐glycine disease. Am J Hum Genet 2024;111(1):82–95. - PMC - PubMed
1. Figueroa KP, Gross C, Buena‐Atienza E, Paul S, Gandelman M, Kakar N, et al. A GGC‐repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy. Nat Genet 2024;56(6):1080–1089. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

MeSH terms

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