Please use this identifier to cite or link to this item:
Full metadata record
DC FieldValueLanguage
dc.contributor.authorRafehi, Haloom-
dc.contributor.authorSzmulewicz, David J-
dc.contributor.authorBennett, Mark F-
dc.contributor.authorSobreira, Nara L M-
dc.contributor.authorPope, Kate-
dc.contributor.authorSmith, Katherine R-
dc.contributor.authorGillies, Greta-
dc.contributor.authorDiakumis, Peter-
dc.contributor.authorDolzhenko, Egor-
dc.contributor.authorEberle, Michael A-
dc.contributor.authorBarcina, María García-
dc.contributor.authorBreen, David P-
dc.contributor.authorChancellor, Andrew M-
dc.contributor.authorCremer, Phillip D-
dc.contributor.authorDelatycki, Martin B-
dc.contributor.authorFogel, Brent L-
dc.contributor.authorHackett, Anna-
dc.contributor.authorHalmagyi, G Michael-
dc.contributor.authorKapetanovic, Solange-
dc.contributor.authorLang, Anthony-
dc.contributor.authorMossman, Stuart-
dc.contributor.authorMu, Weiyi-
dc.contributor.authorPatrikios, Peter-
dc.contributor.authorPerlman, Susan L-
dc.contributor.authorRosemergy, Ian-
dc.contributor.authorStorey, Elsdon-
dc.contributor.authorWatson, Shaun R D-
dc.contributor.authorWilson, Michael A-
dc.contributor.authorZee, David S-
dc.contributor.authorValle, David-
dc.contributor.authorAmor, David J-
dc.contributor.authorBahlo, Melanie-
dc.contributor.authorLockhart, Paul J-
dc.identifier.citationAmerican journal of human genetics 2019; 105(1): 151-165-
dc.description.abstractGenomic 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.-
dc.subjectrepeat expansions-
dc.subjectshort tandem repeats-
dc.subjectwhole-genome sequencing-
dc.titleBioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.-
dc.typeJournal Article-
dc.identifier.journaltitleAmerican journal of human genetics-
dc.identifier.affiliationUniversity of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australiaen
dc.identifier.affiliationDepartment of Medicine, Division of Neurology, University Health Network and the University of Toronto, Toronto, ON M5T 2S8, Canadaen
dc.identifier.affiliationCerebellar Ataxia Clinic, Neuroscience Department, Alfred Health, Melbourne, VIC 3004, Australiaen
dc.identifier.affiliationCentre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, Scotlanden
dc.identifier.affiliationAnne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh EH16 4SB, Scotlanden
dc.identifier.affiliationUsher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH16 4UX, Scotlanden
dc.identifier.affiliationEdmond J. Safra Program in Parkinson disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON M5T 2S8, Canadaen
dc.identifier.affiliationDepartment of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationUniversity of Sydney, Camperdown, NSW 2006, Australiaen
dc.identifier.affiliationBruce Lefroy Centre, Murdoch Children's Research Institute, Flemington Rd, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationHunter Genetics, Hunter New England Health Service, Waratah, Newcastle, NSW 2300, Australiaen
dc.identifier.affiliationNeurology Department, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australiaen
dc.identifier.affiliationDepartment of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Rd, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationCentral Clinical School, University of Sydney, Camperdown, NSW 2050, Australiaen
dc.identifier.affiliationUniversity of Newcastle, Newcastle, NSW 2300, Australiaen
dc.identifier.affiliationRoyal North Shore Hospital, Pacific Hwy, St Leonards, NSW 2065, Australiaen
dc.identifier.affiliationEpilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationBalance Disorders and Ataxia Service, Royal Victorian Eye & Ear Hospital, East Melbourne, VIC 3002, Australiaen
dc.identifier.affiliationInstitute of Neurological Sciences, Prince of Wales Hospital, Randwick, NSW 2031, Australiaen
dc.identifier.affiliationDepartment of Neuroscience, Central Clinical School, Monash University, Alfred Hospital Campus, Commercial Road, Melbourne, VIC 3004, Australiaen
dc.identifier.affiliationSunshine Neurology, Maroochydore, QLD 4558, Australiaen
dc.identifier.affiliationPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA-
dc.identifier.affiliationIllumina Inc, 5200 Illumina Way, San Diego, CA 92122, USA-
dc.identifier.affiliationGenetic Unit, Basurto University Hospital, OSI Bilbao-Basurto, avenida Montevideo 18, 48013 Bilbao, Spain-
dc.identifier.affiliationDepartment of Neurology, Tauranga Hospital, Private Bag, Cameron Road, Tauranga 3171, New Zealand-
dc.identifier.affiliationDepartments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA-
dc.identifier.affiliationServicio de Neurología, Hospital de Basurto, Avenida de Montevideo 18, 48013 Bilbao, Bizkaia, Spain-
dc.identifier.affiliationDepartment of Neurology, Wellington Hospital, Wellington 6021, New Zealand-
dc.identifier.affiliationMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA-
dc.identifier.affiliationDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA-
dc.identifier.affiliationDepartment of Neurology, Wellington Hospital, Newtown, Wellington 6021, New Zealand-
dc.identifier.affiliationDepartment of Neurology, Johns Hopkins Hospital, Baltimore, MD 21287, USA-
dc.identifier.affiliationMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA-
Appears in Collections:Journal articles

Files in This Item:
There are no files associated with this item.

Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.