Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/21138
Title: Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.
Authors: Rafehi, Haloom;Szmulewicz, David J;Bennett, Mark F;Sobreira, Nara L M;Pope, Kate;Smith, Katherine R;Gillies, Greta;Diakumis, Peter;Dolzhenko, Egor;Eberle, Michael A;Barcina, María García;Breen, David P;Chancellor, Andrew M;Cremer, Phillip D;Delatycki, Martin B;Fogel, Brent L;Hackett, Anna;Halmagyi, G Michael;Kapetanovic, Solange;Lang, Anthony;Mossman, Stuart;Mu, Weiyi;Patrikios, Peter;Perlman, Susan L;Rosemergy, Ian;Storey, Elsdon;Watson, Shaun R D;Wilson, Michael A;Zee, David S;Valle, David;Amor, David J;Bahlo, Melanie;Lockhart, Paul J
Affiliation: University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia
Department of Medicine, Division of Neurology, University Health Network and the University of Toronto, Toronto, ON M5T 2S8, Canada
Cerebellar Ataxia Clinic, Neuroscience Department, Alfred Health, Melbourne, VIC 3004, Australia
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, Scotland
Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh EH16 4SB, Scotland
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH16 4UX, Scotland
Edmond J. Safra Program in Parkinson disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada
Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia
University of Sydney, Camperdown, NSW 2006, Australia
Bruce Lefroy Centre, Murdoch Children's Research Institute, Flemington Rd, Parkville, VIC 3052, Australia
Hunter Genetics, Hunter New England Health Service, Waratah, Newcastle, NSW 2300, Australia
Neurology Department, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Rd, Parkville, VIC 3052, Australia
Central Clinical School, University of Sydney, Camperdown, NSW 2050, Australia
University of Newcastle, Newcastle, NSW 2300, Australia
Royal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australia
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Balance Disorders and Ataxia Service, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC 3002, Australia
Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, NSW 2031, Australia
Department of Neuroscience, Central Clinical School, Monash University, Alfred Hospital Campus, Commercial Road, Melbourne, VIC 3004, Australia
Sunshine Neurology, Maroochydore, QLD 4558, Australia
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Illumina Inc, 5200 Illumina Way, San Diego, CA 92122, USA
Genetic Unit, Basurto University Hospital, OSI Bilbao-Basurto, avenida Montevideo 18, 48013 Bilbao, Spain
Department of Neurology, Tauranga Hospital, Private Bag, Cameron Road, Tauranga 3171, New Zealand
Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Servicio de Neurología, Hospital de Basurto, Avenida de Montevideo 18, 48013 Bilbao, Bizkaia, Spain
Department of Neurology, Wellington Hospital, Wellington 6021, New Zealand
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Department of Neurology, Wellington Hospital, Newtown, Wellington 6021, New Zealand
Department of Neurology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Issue Date: 3-Jul-2019
EDate: 2019-06-20
Citation: American journal of human genetics 2019; 105(1): 151-165
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21138
DOI: 10.1016/j.ajhg.2019.05.016
PubMed URL: 31230722
Type: Journal Article
Subjects: CANVAS
ataxia
repeat expansions
short tandem repeats
whole-genome sequencing
Appears in Collections:Journal articles

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