Profiling of somatic, population and phenotypic heterogeneity in genetic causes of ALS/MND

Amyotrophic Lateral Sclerosis (ALS) or Motor Neurone Disease (MND) is a rapidly progressive and universally fatal neurological disorder. While some genetic causes have been discovered, much remains unknown, especially in different populations. Brachial monomelic amyotrophy (MMA) is a rare condition that mimics MND, but with a better prognosis. The genetic basis of MMA is currently unknown. In this study, DNA samples from the motor cortex of ALS cases were genotyped using whole genome sequencing (WGS) to compare results with those previously found in peripheral blood to screen for the presence of somatic mutations. Targeted sequencing of ALS genes in 28 Bangladeshi MND patients, including 11 MMA patients, was performed and compared with results from 8 UK MMA patients to establish if there was genetic link between the two diseases. Two SOD1 and a FUS mutation were found in the motor cortex samples but had previously been found in peripheral blood, not supporting the hypothesis of somatic heterogeneity. Screening of Bangladesh samples revealed 99 variants in 32 ALS risk genes, including pathogenic SOD1 mutations in 3 patients. Forty-three variants of conflicting interpretations (n=17), uncertain significance (n=12), risk factor (n=1) and unknown (n=13) were found in MMA patients, highlighting a shared genetic basis of MMA and MND. This is supported by the presence of TDP-43 pathology in UK MMA patient samples. The study discovered the genetic basis of MND in Bangladesh was overlapping but distinct compared to the UK, with no C9ORF72 mutations found in the Bangladeshi MND cases. Further work is needed to validate the variants currently designated as variants of uncertain significance in both MMA and MND patients.