Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which has a high degree of genetic variability with dozens of different genes and hundreds of unique genetic alterations implicated in disease. We complied a comprehensive catalogue of these alterations totalling 853, and interrogated DNA sequences from 616 Australian patients without a family history of ALS for the presence of these alterations. We confirmed that genetic predisposition contributes to ALS in cases where there is no obvious family history, by identifying forty-three unique genetic alterations from 18 different genes in over one third of patients. We also found over 6% of patients carried two or more ALS-linked genetic alterations, and that these patients were more likely to develop ALS earlier in life than patients with no genetic alterations, suggesting multiple genetic alterations interact to contribute to the cause, and influence the clinical manifestation, of ALS. (By Dr. Emily McCann, https://jmg.bmj.com/content/early/2020/05/14/jmedgenet-2020-106866 )