Haloom Rafehi1,2,3, David J Szmulewicz4,5, Kate Pope6, Mathew Wallis7,8, John Christodoulou9,10, Susan M White10,11,12, Martin B Delatycki6,10,11, Paul J Lockhart6,10, Melanie Bahlo1,2. 1. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. 2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. 3. Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia. 4. Cerebellar Ataxia Clinic, Neuroscience Department, Alfred Health, Melbourne, Victoria, Australia. 5. Balance Disorders and Ataxia Service, Royal Victorian Eye & Ear Hospital, East Melbourne, Victoria, Australia. 6. Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia. 7. Tasmanian Clinical Genetics Service, Tasmanian Health Service, Tasmania, Australia. 8. School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia. 9. Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia. 10. Department of Pediatrics, The University of Melbourne, Parkville, Victoria, Australia. 11. Victorian Clinical Genetics Services, Parkville, Victoria, Australia. 12. Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Abstract
BACKGROUND: Spinocerebellar ataxias are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion (RE) detection with whole-genome sequencing (WGS) feasible. OBJECTIVES: The objective of this study was to determine the genetic basis of ataxia in a multigenerational Australian pedigree with autosomal-dominant inheritance. METHODS AND RESULTS: WGS was performed on 3 affected relatives. The sequence data were screened for known pathogenic REs using 2 RE detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of spinocerebellar ataxia 36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. CONCLUSIONS: The diagnosis of rare ataxias caused by REs is highly feasible and cost-effective with WGS. We propose that WGS could potentially be implemented as the frontline, cost-effective methodology for the molecular testing of individuals with a clinical diagnosis of ataxia.
BACKGROUND:Spinocerebellar ataxias are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion (RE) detection with whole-genome sequencing (WGS) feasible. OBJECTIVES: The objective of this study was to determine the genetic basis of ataxia in a multigenerational Australian pedigree with autosomal-dominant inheritance. METHODS AND RESULTS: WGS was performed on 3 affected relatives. The sequence data were screened for known pathogenic REs using 2 RE detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of spinocerebellar ataxia 36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. CONCLUSIONS: The diagnosis of rare ataxias caused by REs is highly feasible and cost-effective with WGS. We propose that WGS could potentially be implemented as the frontline, cost-effective methodology for the molecular testing of individuals with a clinical diagnosis of ataxia.
Authors: Kristina Ibañez; James Polke; R Tanner Hagelstrom; Egor Dolzhenko; Dorota Pasko; Ellen Rachel Amy Thomas; Louise C Daugherty; Dalia Kasperaviciute; Katherine R Smith; Zandra C Deans; Sue Hill; Tom Fowler; Richard H Scott; John Hardy; Patrick F Chinnery; Henry Houlden; Augusto Rendon; Mark J Caulfield; Michael A Eberle; Ryan J Taft; Arianna Tucci Journal: Lancet Neurol Date: 2022-03 Impact factor: 59.935