Volume 176, 2024, Pages 49-74Author links open overlay panel, , Abstract

ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.

Section snippetsMendelian risk genes and familial ALS

There is no doubt that ALS has a genetic component. Research is now focussed on identifying the nature of the genetic contribution, and its extent. Does every person with ALS have a genetic predisposition, with the only distinction being the size of the effect, or do some people develop ALS with no apparent genetic component at all? In this chapter, we will explore the genetics of ALS, what is currently known, and what remains to be answered.

ALS is commonly categorized as familial or sporadic,

Genetic testing

The identification of ALS gene variants helps us to understand disease mechanisms and thereby potentially identify new treatments. It may also reveal diagnostic, target engagement, prognostic, stage or treatment response biomarkers. However, understanding ALS genetics also has important consequences for individuals. The most straightforward is that finding an ALS gene variant in a family with multiple affected individuals provides a means by which people at risk may be identified if they wish.

Glossary of termsPhenotype

Any characteristic of an individual, but usually taken to mean characteristics resulting from a genotype.

Genotype

The nucleotides at a specific genomic position (could be identical to the reference genome or could be a variant).

Locus (plural: loci)

A genetic address may be defined by a gene name, an ID number (often beginning rs) or a chromosome number and base pair position, accompanied by the specific build of genome being referenced.

Penetrance

The probability of a phenotype given a

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