ALS genetics are highly dynamic and of great interest for the ALS research community. Each year, by using ever-growing datasets and cutting-edge methodology, an array of novel ALS-associated genes and downstream pathomechanisms are discovered. The increasing plenty and complexity of insights warrants regular summary by-reviews.

Most recent disease gene discoveries constitute the candidate and risk genes SPTLC1, KANK1, CAV1, HTT, and WDR7, as well as seven novel risk loci. Cell type and functional enrichment analyses enlighten the genetic basis of selective motor neuron vulnerability in ALS demonstrating high expression of ALS-associated genes in cortical motor neurons and highlight the pathogenic significance of cell-autonomous processes. Major pathomechanistic insights have been gained regarding known ALS genes/proteins, specifically C9orf72, TDP43, ANXA11, and KIF5A. The first ASO-based gene-specific therapy trials in familial forms of ALS have yielded equivocal results stressing the re-evaluation of pathomechanisms linked to SOD1 and C9orf72 mutations.

The genetic and molecular basis of ALS is increasingly examined on single-cell resolution. In the past 2 years, the understanding of the downstream mechanisms of several ALS genes and TDP-43 proteinopathy has been considerably extended. These insights will result in novel gene specific therapy approaches for sporadic ALS and genetic subtypes.