Amyotrophic lateral sclerosis (ALS) is a syndrome that can result from many possible underlying genetic variations; the rate of gene discovery in ALS is doubling every 4 years
ALS has a genetic archtecture in which a few rare variants contribute to risk in each patient, rather than a polygenic architecture whereby the cumulative effects of many common variants increase risk
Carrying a disease mutation does not inevitably lead to ALS, and many ALS-associated genes are also implicated in other conditions, including frontotemporal dementia and cerebellar disease
The distinction between familial and sporadic ALS is not clear-cut, which greatly complicates genetic counselling in ALS
Current data are consistent with a model in which multiple molecular steps are required to cause ALS; the causes of these steps could be genetic or environmental
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly affecting upper and lower motor neurons. The disease leads to relentlessly progressive weakness of voluntary muscles, with death typically resulting from diaphragmatic failure within 2–5 years. Since the discovery of mutations in SOD1, which account for ∼2% of ALS cases, increasing efforts have been made to understand the genetic component of ALS risk, with the expectation that this insight will not only aid diagnosis and classification, but also guide personalized treatment and reveal the mechanisms that cause motor neuron death. In this Review, we outline previous and current efforts to characterize genes that are associated with ALS, describe current knowledge about the genetic architecture of ALS — including the relevance of family history — and the probable nature of future gene discoveries, and explore how our understanding of ALS genetics affects present and future clinical decisions. We observe that many gene variants associated with ALS have effect sizes between those of mutations that greatly increase risk and those of common variants that have a small effect on risk, and combine this observation with insights from next-generation sequencing to explore the implications for genetic counselling.
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The authors would like to thank The EU Joint Programme — Neurodegenerative Disease Research (JPND) projects: STRENGTH, SOPHIA and ALS-CarE. The authors' work is supported by the following funding organizations under the aegis of JPND: the Medical Research Council and the Economic and Social Research Council in the UK, and ZonMW in the Netherlands. A.A.-C. receives salary support from the National Institute for Health Research Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London, UK. The work leading up to this publication was funded by the European Community's Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Programme (H2020-PHC-2014-two-stage; grant agreement number 633413). The authors would also like to thank Dr William Sproviero who kindly provided the data used in Fig. 2. The authors' work is supported by ZonMW under the frame of E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID).
A.A.-C. declares associations with OrionPharma, Cytokinetics, Mitsubishi-Tanabe Pharma, OneWorld Publications and Cold Spring Harbor Laboratory Press. L.H.B. received a grant from the Netherlands Organization for Health Research and Development (Vici scheme); serves on scientific advisory boards for Prinses Beatrix Spierfonds, Thierry Latran Foundation, Baxalta, Cytokinetics and Biogen. J.V. declares no competing interests.
A statistical technique whereby the transmission and sharing of genetic variations within a family is used to home in on the disease gene. Linkage analysis is conducted by comparing the observed frequency of transmissions with the pattern that would be expected if there was no relationship with disease status.
- Somatic mosaicism
Mutations that arise during mitotic cell division are inherited in all the daughter cells of that line. Although individual mutations are rare, human cells undergo so many divisions that we are all mosaics of cells that are nearly, but not quite, genetically identical.
The conditional probability of a phenotype, such as amyotrophic lateral sclerosis, being associated with a given genotype.
- El Escorial criteria
Research criteria used to define the certainty that the phenotype will ultimately be amyotrophic lateral sclerosis rather than some other variant of motor neuron disease. The criteria are based on the distribution and pattern of upper and lower motor neuron signs, and have recently been revised to incorporate neurophysiological findings.
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Al-Chalabi, A., van den Berg, L. & Veldink, J. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat Rev Neurol 13, 96–104 (2017). https://doi.org/10.1038/nrneurol.2016.182
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