Oligogenic basis of sporadic ALS: The example of p.Ala90Val mutation.

Objective: To characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 () p.Ala90Val mutation, as well as the mutation frequency and the role of oligogenic mechanisms in disease penetrance.

Methods: An index patient with autopsy-proven ALS was discovered to have the p.Ala90Val mutation, which was screened in 2 Finnish ALS cohorts (n = 453). Additional contributing variants were analyzed from whole-genome or whole-exome sequencing data.

Results: Seven screened patients (1.5%) were found to carry the heterozygous mutation. Allele-sharing analysis suggested a common founder haplotype. Common clinical features included limb-onset, long disease course, and sensory symptoms. No TDP43 pathology was observed. All cases were apparently sporadic, and pedigree analysis demonstrated that the mutation has reduced penetrance. Analysis of other contributing genes revealed a unique set of additional variants in each patient. These included previously described rare and mutations. One patient was compound heterozygous for p.Ala90Val and p.Asp91Ala.

Conclusions: Our data suggest that the penetrance of p.Ala90Val is modulated by other genes and indicates highly individual oligogenic basis of apparently sporadic ALS. Additional genetic variants likely contributing to disease penetrance were very heterogeneous, even among Finnish patients carrying the founder mutation.