Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS
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Abstract
Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 ( RFC1 ). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1 -negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
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A new algorithm can detect alternative repeat motifs from genome sequence.
“but a novel algorithm can now detect them from genome sequence28.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [28]
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- Authors
- Rafehi, H., Szmulewicz, D. J., Bennett, M. F., Sobreira, N. L. M., Pope, K., Smith, K. R., Gillies, G., Diakumis, P., Dolzhenko, E., Eberle, M. A., Barcina, M. G., Breen, D. P., Chancellor, A. M., Cremer, P. D., Delatycki, M. B., Fogel, B. L., Hackett, A., Halmagyi, G. M., Kapetanovic, S., Lang, A., Mossman, S., Mu, W., Patrikios, P., Perlman, S. L., Rosemergy, I., Storey, E., Watson, S. R. D., Wilson, M. A., Zee, D. S., Valle, D., Amor, D. J., Bahlo, M., & Lockhart, P. J.
- Affiliations
- The University of Melbourne (AU)
- The Alfred Hospital (AU)
- Johns Hopkins University (US)
- Murdoch Children's Research Institute (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Illumina (United States) (US)
- Hospital de Basurto (ES)
- MRC Centre for Regenerative Medicine (GB)
- Tauranga Hospital (NZ)
- The University of Sydney (AU)
- Royal Children's Hospital (AU)
- University of California, Los Angeles (US)
- Hunter Genetics (AU)
- University Health Network (CA)
- Wellington Hospital (NZ)
- Prince of Wales Hospital (AU)
- Corresponding author
- Lockhart, Paul J.
- ORCID
- Rafehi, Haloom
- Szmulewicz, David J.
- Bennett, Mark F.
- Pope, Kate
- Smith, Katherine R.
- Diakumis, Peter
- Dolzhenko, Egor
- Eberle, Michael A.
- Breen, David P.
- Chancellor, Andrew M.
- Delatycki, Martin B.
- Fogel, Brent L.
- Hackett, Anna
- Halmagyi, G. Michael
- Kapetanovic, Solange
- Lang, Anthony
- Mossman, Stuart
- Mu, Weiyi
- Perlman, Susan L.
- Rosemergy, Ian
- Storey, Elsdon
- Watson, Shaun R.D.
- Zee, David S.
- Valle, David
- Amor, David J.
- Bahlo, Melanie
- Lockhart, Paul J.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 105
- Issue
- 1
- Pages
- 151-165
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC6612533
- OpenAlex
- W2951000946
- Cited by
- 262
- References
- 63
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 51 · 2023: 37 · 2022: 49 · 2021: 31 · 2020: 39 · 2019: 9 · 2012: 1
- FWCI
- 15.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- NOVA (University of Newcastle Australia) (submittedVersion, cc-by)
- Funders
- Australian Government National Health and Medical Research Council (1054618)
- NIH (R01NS082094)
- Murdoch Children’s Research Institute
- NHMRC Senior Research Fellowship (1102971)
- Wellcome Clinical Research Career Development Fellowship
- Independent Research Institute Infrastructure Support Scheme
- Victorian State Government Operational Infrastructure Program
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- CANVAS syndrome, intronic repeat expansion, RFC1, Alu elements, microsatellite markers, whole genome sequencing, recessive inheritance, ancestral haplotypes, spinocerebellar ataxia type 3, neurogenetic disorders, molecular diagnosis
- MeSH terms
- Whole Genome Sequencing, Algorithms, Cerebellar Ataxia, Family, Female, Humans, Introns, Male, Middle Aged, Polyneuropathies, Sensation Disorders, Syndrome, Cohort Studies, Vestibular Diseases, Microsatellite Repeats, Computational Biology, Genomics, Replication Protein C
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