ALS Genes in the Genomic Era and their Implications for FTD

Highlights

High-throughput DNA sequencing, including whole-genome and -exome sequencing, has proven a successful strategy for gene identification in ALS.

Substantial progress in gene identification revealed recurrent key molecular mechanisms in ALS, including proteostasis and autophagy, RNA processing, cytoskeleton dynamics, mitochondrial dysfunction, and DNA damage response.

ALS and FTD are partners of one disease continuum, consequently gene identification in ALS is impacting FTD genetic etiology and vice versa.

The emerging concept of oligogenic inheritance in ALS, and possibly also in FTD, has implications on gene identification, genetic testing, and genetic counseling, as well as therapy development.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient–control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy.