Reduced penetrance of gene variants causing amyotrophic lateral sclerosis

Abstract

BackgroundAmyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes areC9orf72,SOD1,TARDBPandFUS. Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level.ObjectiveWe sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis.MethodsPublished epidemiological data for amyotrophic lateral sclerosis and frontotemporal dementia were used to calculate expected frequencies of disease-causing variants per gene at population level. Variant data from gnomAD and ClinVar databases were used to ascertain observed numbers of disease-causing variants and to estimate population-level penetrance per gene. Data forC9orf72were obtained from the published literature.ResultsMaximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% forC9orf72(95% CI (20.9 to 53.2)), 54% forSOD1(95% CI (32.7 to 88.6)), 38% forTARDBP(95% CI (21.1 to 69.8)) and 19% forFUS(95% CI (13.0 to 28.4)).ConclusionPopulation-level penetrance of amyotrophic lateral sclerosis disease genes is reduced. This finding has implications for the genetic testing and counselling of affected individuals and their unaffected relatives.