Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4.

ataxia long-read sequencing repeat expansion disorder

Journal

Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688

Informations de publication

Date de publication:
10 Jan 2024
Historique:
revised: 29 11 2023
received: 03 11 2023
accepted: 15 12 2023
medline: 10 1 2024
pubmed: 10 1 2024
entrez: 10 1 2024
Statut: aheadofprint

Résumé

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) 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.

Sections du résumé

BACKGROUND BACKGROUND
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.
OBJECTIVES OBJECTIVE
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.
METHODS METHODS
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.
RESULTS RESULTS
Using this approach, we found a heterozygous (GGC)
CONCLUSIONS CONCLUSIONS
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.

Identifiants

DOI: 10.1002/mds.29704 PMID: 38197134
pubmed: 38197134
doi: 10.1002/mds.29704
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : MRC
Organisme : Leonard Wolfson Foundation

Informations de copyright

© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Références

Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A. GeneReviews® [Internet]; 1993.
Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Primers 2019;5:24.
Sullivan R, Yau WY, O'Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol 2019;266:533-544.
Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet 2019;51:649-658. https://doi.org/10.1038/s41588-019-0372-4
Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, et al. Deep Intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med 2023;388:128-141. https://doi.org/10.1056/NEJMoa2207406
Flanigan K, Gardner K, Alderson K, 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;59:392-399.
Hellenbroich Y, Pawlack H, Rüb U, Schwinger E, Zühlke C. Spinocerebellar ataxia type 4. J Neurol 2005;252:1472-1475. https://doi.org/10.1007/s00415-005-0892-y
Hellenbroich Y, Bubel S, Pawlack H, Opitz S, Vieregge P, Schwinger E, Zühlke C. Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region. J Neurol 2003;250:668-671. https://doi.org/10.1007/s00415-003-1052-x
Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T. Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet 2009;85:544-557. https://doi.org/10.1016/j.ajhg.2009.09.019
Tan D, Wei C, Chen Z, Huang Y, Deng J, Li J, et al. CAG repeat expansion in THAP11 is associated with a novel spinocerebellar ataxia. Mov Disord 2023;38:1282-1293. https://doi.org/10.1002/mds.29412
Miller DE, Sulovari A, Wang T, Loucks H, Hoekzema K, Munson KM, et al. Targeted long-read sequencing identifies missing disease-causing variation. Am J Hum Genet 2021;108:1436-1449. https://doi.org/10.1016/j.ajhg.2021.06.006
Mölder F, Jablonski KP, Letcher B, Hall MB, Tomkins-Tinch CH, Sochat V, et al. Sustainable data analysis with Snakemake. F1000Res 2021;10:33. https://doi.org/10.12688/f1000research.29032.2
De Coster W, D'Hert S, Schultz DT, Cruts M, Van Broeckhoven C. NanoPack: visualizing and processing long-read sequencing data. Bioinformatics 2018;34:2666-2669. https://doi.org/10.1093/bioinformatics/bty149
Li H. Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics 2018;34:3094-3100. https://doi.org/10.1093/bioinformatics/bty191
Sedlazeck FJ, Rescheneder P, Smolka M, Fang H, Nattestad M, von Haeseler A, Schatz MC. Accurate detection of complex structural variations using single-molecule sequencing. Nat Methods 2018;15:461-468. https://doi.org/10.1038/s41592-018-0001-7
Smedley D, Smith KR, Martin A, Thomas EA, McDonagh EM, Cipriani V, et al. 100,000 genomes pilot on rare-disease diagnosis in health care - preliminary report. N Engl J Med 2021;385:1868-1880. https://doi.org/10.1056/NEJMoa2035790
Dolzhenko E, Deshpande V, Schlesinger F, Krusche P, Petrovski R, Chen S, et al. ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions. Bioinformatics 2019;35:4754-4756. https://doi.org/10.1093/bioinformatics/btz431
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science 2015;347:1260419. https://doi.org/10.1126/science.1260419
Chen Z, Tucci A, Cipriani V, Gustavsson EK, Ibañez K, Reynolds RH, et al. Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia. Brain 2023;146:2869-2884. https://doi.org/10.1093/brain/awad009
Benson G. Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 1999;27:573-580. https://doi.org/10.1093/nar/27.2.573
Willems T, Zielinski D, Yuan J, Gordon A, Gymrek M, Erlich Y. Genome-wide profiling of heritable and de novo STR variations. Nat Methods 2017;14:590-592. https://doi.org/10.1038/nmeth.4267
Cunningham F, Allen JE, Allen J, Alvarez-Jarreta J, Amode MR, Armean IM, et al. Ensembl 2022. Nucleic Acids Res 2021;50:D988-D995. https://doi.org/10.1093/nar/gkab1049
Martin AR, Williams E, Foulger RE, Leigh S, Daugherty LC, Niblock O, et al. PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet 2019;51:1560-1565. https://doi.org/10.1038/s41588-019-0528-2
Maschke M, Oehlert G, Xie TD, et al. Clinical feature profile of spinocerebellar ataxia type 1-8 predicts genetically defined subtypes. Mov Disord 2005;20:1405-1412. https://doi.org/10.1002/mds.20533
MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res 2014;42:D986-D992. https://doi.org/10.1093/nar/gkt958
Ibañez K, Polke J, Hagelstrom RT, Dolzhenko E, Pasko D, Thomas ERA, et al. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol 2022;21:234-245. https://doi.org/10.1016/s1474-4422(21)00462-2
Chen Z, Tucci A, Ryten M. Deep Intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med 2023;388:e70. https://doi.org/10.1056/NEJMc2301605
Jam HZ, Li Y, DeVito R, Mousavi N, Ma N, Lujumba I, et al. A deep population reference panel of tandem repeat variation. bioRxiv 2023. https://doi.org/10.1101/2023.03.09.531600
Morinaga T, Yasuda H, Hashimoto T, Higashio K, Tamaoki T. A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers. Mol Cell Biol 1991;11:6041-6049.
Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet 2009;41:879-881. https://doi.org/10.1038/ng.416.
Parsons MJ, Brancaccio M, Sethi S, Maywood ES, Satija R, Edwards JK, et al. The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven Axis. Cell 2015;162:607-621. https://doi.org/10.1016/j.cell.2015.06.060
Del Rocío Pérez Baca M, Jacobs EZ, Vantomme L, Leblanc P, Bogaert E, Dheedene A, et al. A novel neurodevelopmental syndrome caused by loss-of-function of the zinc finger Homeobox 3 (ZFHX3) gene. medRxiv 2023;2023.2005.2022.23289895. https://doi.org/10.1101/2023.05.22.23289895
Osseward PJ, Amin ND, Moore JD, Temple BA, Barriga BK, Bachmann LC, et al. Conserved genetic signatures parcellate cardinal spinal neuron classes into local and projection subsets. Science 2021;372:385-393. https://doi.org/10.1126/science.abe0690
Boivin M, Deng J, Pfister V, Grandgirard E, Oulad-Abdelghani M, Morlet B, et al. Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: the polyG diseases. Neuron 2021;109:1825-1835.e1825. https://doi.org/10.1016/j.neuron.2021.03.038
Gelpi E, Botta-Orfila T, Bodi L, Marti S, Kovacs G, Grau-Rivera O, et al. Neuronal intranuclear (hyaline) inclusion disease and fragile X-associated tremor/ataxia syndrome: a morphological and molecular dilemma. Brain 2017;140:e51. https://doi.org/10.1093/brain/awx156
Hellenbroich Y, Gierga K, Reusche E, et al. Spinocerebellar ataxia type 4 (SCA4): initial pathoanatomical study reveals widespread cerebellar and brainstem degeneration. J Neural Transm (Vienna) 2006;113:829-843. https://doi.org/10.1007/s00702-005-0362-9

Auteurs

Zhongbo Chen (Z)

Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, United Kingdom.
ORCID: 0000-0001-6668-7202

Emil K Gustavsson (EK)

Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, United Kingdom.

Hannah Macpherson (H)

Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Claire Anderson (C)

Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, United Kingdom.

Chris Clarkson (C)

William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.

Clarissa Rocca (C)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.

Eleanor Self (E)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.

Pilar Alvarez Jerez (P)

Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.
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.

Annarita Scardamaglia (A)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.

David Pellerin (D)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.

Kylie Montgomery (K)

Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, United Kingdom.

Jasmaine Lee (J)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.

Delia Gagliardi (D)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.

Huihui Luo (H)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.

John Hardy (J)

Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.
Reta Lila Weston Institute, Queen Square Institute of Neurology, University College London, London, United Kingdom.
UK Dementia Research Institute, University College London, London, United Kingdom.
NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom.
Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China.

James Polke (J)

The Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom.

Andrew B Singleton (AB)

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.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Cornelis Blauwendraat (C)

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.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
ORCID: 0000-0001-9358-8111

Katherine D Mathews (KD)

Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

Arianna Tucci (A)

William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.

Ying-Hui Fu (YH)

Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
Weill Institute for Neuroscience, University of California San Francisco, San Francisco, California, USA.
Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, California, USA.

Henry Houlden (H)

Department of Neuromuscular Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom.
The Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
ORCID: 0000-0002-2866-7777

Mina Ryten (M)

Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, United Kingdom.

Louis J Ptáček (LJ)

Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
Weill Institute for Neuroscience, University of California San Francisco, San Francisco, California, USA.
Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, California, USA.

Classifications MeSH