RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics.

Autor:	Scriba CK; Rare Genetic Diseases and Functional Genomics Group, Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia.; Neurogenetics Laboratory, Department of Diagnostic Genomics, PP Block, QEII Medical Centre, Nedlands, WA 6009, Australia., Stevanovski I; Genomics Pillar, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW 2010, Australia., Chintalaphani SR; Genomics Pillar, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2050, Australia., Gamaarachchi H; Genomics Pillar, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW 2010, Australia.; School of Computer Science and Engineering, University of New South Wales, Sydney, NSW 2052, Australia., Ghaoui R; Department of Neurology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia., Ghia D; UWA Medical School, University of Western Australia, Perth, WA 6009, Australia.; Neurology and Stroke Unit, Fiona Stanley Hospital, Murdoch, WA 6150, Australia., Henderson RD; Centre for Clinical Research, University of Queensland, Herston, QLD 4006, Australia., Jordan N; Department of Neurology, Fiona Stanley Hospital, Perth, WA 6150, Australia., Winkel A; Department of Neurosciences, Griffith University, Sunshine Coast University Hospital, Mount Gravatt, QLD 4111, Australia., Lamont PJ; Neurogenetic Unit, Royal Perth Hospital, Perth, WA 6000, Australia., Rodrigues MJ; Neurology Department, Auckland City Hospital, Auckland, New Zealand., Roxburgh RH; Centre for Brain Research Neurogenetics Research Clinic, University of Auckland, Auckland, New Zealand., Weisburd B; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Laing NG; Preventive Genetics Group, Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia., Deveson IW; Genomics Pillar, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW 2010, Australia.; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2050, Australia., Davis MR; Neurogenetics Laboratory, Department of Diagnostic Genomics, PP Block, QEII Medical Centre, Nedlands, WA 6009, Australia., Ravenscroft G; Rare Genetic Diseases and Functional Genomics Group, Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2023 Jul 25; Vol. 5 (4), pp. fcad208. Date of Electronic Publication: 2023 Jul 25 (Print Publication: 2023).
DOI:	10.1093/braincomms/fcad208
Abstrakt:	Cerebellar ataxia, neuropathy and vestibular areflexia syndrome is a progressive, generally late-onset, neurological disorder associated with biallelic pentanucleotide expansions in Intron 2 of the RFC1 gene. The locus exhibits substantial genetic variability, with multiple pathogenic and benign pentanucleotide repeat alleles previously identified. To determine the contribution of pathogenic RFC1 expansions to neurological disease within an Australasian cohort and further investigate the heterogeneity exhibited at the locus, a combination of flanking and repeat-primed PCR was used to screen a cohort of 242 Australasian patients with neurological disease. Patients whose data indicated large gaps within expanded alleles following repeat-primed PCR, underwent targeted long-read sequencing to identify novel repeat motifs at the locus. To increase diagnostic yield, additional probes at the RFC1 repeat region were incorporated into the PathWest diagnostic laboratory targeted neurological disease gene panel to enable first-pass screening of the locus for all samples tested on the panel. Within the Australasian cohort, we detected known pathogenic biallelic expansions in 15.3% ( n = 37) of patients. Thirty indicated biallelic AAGGG expansions, two had biallelic 'Māori alleles' [(AAAGG) exp (AAGGG) exp ], two samples were compound heterozygous for the Māori allele and an AAGGG expansion, two samples had biallelic ACAGG expansions and one sample was compound heterozygous for the ACAGG and AAGGG expansions. Forty-five samples tested indicated the presence of biallelic expansions not known to be pathogenic. A large proportion (84%) showed complex interrupted patterns following repeat-primed PCR, suggesting that these expansions are likely to be comprised of more than one repeat motif, including previously unknown repeats. Using targeted long-read sequencing, we identified three novel repeat motifs in expanded alleles. Here, we also show that short-read sequencing can be used to reliably screen for the presence or absence of biallelic RFC1 expansions in all samples tested using the PathWest targeted neurological disease gene panel. Our results show that RFC1 pathogenic expansions make a substantial contribution to neurological disease in the Australasian population and further extend the heterogeneity of the locus. To accommodate the increased complexity, we outline a multi-step workflow utilizing both targeted short- and long-read sequencing to achieve a definitive genotype and provide accurate diagnoses for patients. Competing Interests: H.G. has previously received travel and accommodation expenses from ONT to speak at conferences. H.G. and I.W.D. have paid consultant roles with Sequin Pty Ltd. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu