Identity by descent analysis identifies founder events and links SOD1 familial and sporadic ALS cases

Lyndal Henden,Dominic B Rowe,Natalie A Twine,Emily P Mccann,Piotr Szul,Ian P Blair,Garth A Nicholson,Denis C Bauer,Matthew C Kiernan,Kelly L Williams

doi:10.1038/s41525-020-00139-8

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by the loss of upper and lower motor neurons resulting in paralysis and eventual death. Approximately 10% of ALS cases have a family history of disease, while the remainder present as apparently sporadic cases. Heritability studies suggest a significant genetic component to sporadic ALS, and although most sporadic cases have an unknown genetic aetiology, some familial ALS mutations have also been found in sporadic cases. This suggests that some sporadic cases may be unrecognised familial cases with reduced disease penetrance in their ancestors. A powerful strategy to uncover a familial link is identity-by-descent (IBD) analysis, which detects genomic regions that have been inherited from a common ancestor. IBD analysis was performed on 83 Australian familial ALS cases from 25 families and three sporadic ALS cases, each of whom carried one of three SOD1 mutations (p.I114T, p.V149G and p.E101G). We defined five unique 350-SNP haplotypes that carry these mutations in our cohort, indicative of five founder events. This included two founder haplotypes that carry SOD1 p.I114T; linking familial and sporadic cases. We found that SOD1 p.E101G arose independently in each family that carries this mutation and linked two families that carry SOD1 p.V149G. The age of disease onset varied between cases that carried each SOD1 p.I114T haplotype. Linking families with identical ALS mutations allows for larger sample sizes and increased statistical power to identify putative phenotypic modifiers.

Highlights

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterised by the progressive loss of upper and lower motor neurons in the motor cortex, brainstem and spinal cord, resulting in paralysis and death, typically from respiratory failure, within 3–5 years of disease onset[1,2,3,4,5]
We analysed a cohort of Australian ALS cases with causal mutation identified as SOD1 p.I114T, p.V149G and p
As each of these three mutations appeared in multiple individuals from different families, we sought to determine if each mutation descended from one or more common ancestor

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterised by the progressive loss of upper and lower motor neurons in the motor cortex, brainstem and spinal cord, resulting in paralysis and death, typically from respiratory failure, within 3–5 years of disease onset[1,2,3,4,5]. Genetic mutations that are present in familial ALS cases have been found in sporadic ALS cases[10,11], suggesting that some sporadic cases may be unrecognised familial cases, perhaps due to reduced disease penetrance in their ancestors. The most common SOD1 mutation in North America is p.A5V (c.14C>T), whereas in Scandinavia and the United Kingdom the most common SOD1 mutations are p.D91A (c.272A>C) and p.I114T (c.341T>C), respectively. All three of these SOD1 mutations, as well as SOD1 p.D12Y (c.34G>T) and p.R116G (c.346C>G), originated from founder events where the mutation descended from a common ancestor[11,13,14,15,16,17]

Methods

Results

Conclusion