Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges

•Amyotrophic lateral sclerosis constitutes a heterogeneous neurodegenerative disorder.•Genetics factors play a significant role in ALS etiology and pathogenesis.•Genetic causes of ~65% of familial and ~10% of sporadic ALS have been identified.•Different genetic mechanisms underlie ALS etiology.•NGS techniques may favor the discovery of new genes.

The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses.This article is part of a Special Issue entitled ALS complex pathogenesis.