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

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 threeSOD1mutations (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 carrySOD1p.I114T; linking familial and sporadic cases. We found thatSOD1p.E101G arose independently in each family that carries this mutation and linked two families that carrySOD1p.V149G. The age of disease onset varied between cases that carried eachSOD1p.I114T haplotype. Linking families with identical ALS mutations allows for larger sample sizes and increased statistical power to identify putative phenotypic modifiers.