Structural Variants May Be a Source of Missing Heritability in sALS

Frances Theunissen; Loren L Flynn; Ryan S Anderton; Frank Mastaglia; Julia Pytte; Leanne Jiang; Stuart Hodgetts; Daniel K Burns; Ann Saunders; Sue Fletcher; Steve D Wilton; Patrick Anthony Akkari

doi:10.3389/fnins.2020.00047

Structural Variants May Be a Source of Missing Heritability in sALS

Front Neurosci. 2020 Jan 31:14:47. doi: 10.3389/fnins.2020.00047. eCollection 2020.

Authors

Frances Theunissen^{1

2}, Loren L Flynn^{1

3

4}, Ryan S Anderton^{1

3

5}, Frank Mastaglia^{1

3}, Julia Pytte^{1

2}, Leanne Jiang^{1

6}, Stuart Hodgetts^{1

2}, Daniel K Burns⁷, Ann Saunders⁷, Sue Fletcher^{3

4}, Steve D Wilton^{1

3

4}, Patrick Anthony Akkari^{1

3

4}

Affiliations

¹ Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
² School of Human Sciences, University of Western Australia, Nedlands, WA, Australia.
³ Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia.
⁴ Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia.
⁵ School of Health Sciences, Institute for Health Research, University of Notre Dame Australia, Fremantle, WA, Australia.
⁶ School of Biological Sciences, University of Western Australia, Nedlands, WA, Australia.
⁷ Zinfandel Pharmaceuticals, Chapel Hill, NC, United States.

Abstract

The underlying genetic and molecular mechanisms that drive amyotrophic lateral sclerosis (ALS) remain poorly understood. Structural variants within the genome can play a significant role in neurodegenerative disease risk, such as the repeat expansion in C9orf72 and the tri-nucleotide repeat in ATXN2, both of which are associated with familial and sporadic ALS. Many such structural variants reside in uncharacterized regions of the human genome, and have been under studied. Therefore, characterization of structural variants located in and around genes associated with ALS could provide insight into disease pathogenesis, and lead to the discovery of highly informative genetic tools for stratification in clinical trials. Such genomic variants may provide a deeper understanding of how gene expression can affect disease etiology, disease severity and trajectory, patient response to treatment, and may hold the key to understanding the genetics of sporadic ALS. This article outlines the current understanding of amyotrophic lateral sclerosis genetics and how structural variations may underpin some of the missing heritability of this disease.

Keywords: amyotrophic lateral sclerosis; clinical trial stratification; genetic marker; missing heritability; structural variant.