Rapid Diagnosis of Spinocerebellar Ataxia 36 in a Three-Generation Family Using Short-Read Whole-Genome Sequencing Data

Haloom Rafehi; David J Szmulewicz; Kate Pope; Mathew Wallis; John Christodoulou; Susan M White; Martin B Delatycki; Paul J Lockhart; Melanie Bahlo

doi:10.1002/mds.28105

Rapid Diagnosis of Spinocerebellar Ataxia 36 in a Three-Generation Family Using Short-Read Whole-Genome Sequencing Data

Mov Disord. 2020 Sep;35(9):1675-1679. doi: 10.1002/mds.28105. Epub 2020 May 14.

Authors

Haloom Rafehi^{1

2

3}, David J Szmulewicz^{4

5}, Kate Pope⁶, Mathew Wallis^{7

8}, John Christodoulou^{9

10}, Susan M White^{10

11

12}, Martin B Delatycki^{6

10

11}, Paul J Lockhart^{6

10}, Melanie Bahlo^{1

2}

Affiliations

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.

PMID: 32407596
DOI: 10.1002/mds.28105

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. © 2020 International Parkinson and Movement Disorder Society.

Keywords: ataxia; diagnosis; exSTRa; repeat expansions; short tandem repeats.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ataxia
Australia
Humans
Microsatellite Repeats
Pedigree
Spinocerebellar Ataxias* / diagnosis
Spinocerebellar Ataxias* / genetics
Whole Genome Sequencing