Reduced penetrance of gene variants causing amyotrophic lateral sclerosis
Reduced penetrance of gene variants causing amyotrophic lateral sclerosis
Background: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are C9orf72, SOD1, TARDBP and FUS. Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level. Objective: We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis. Methods: Published 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 for C9orf72 were obtained from the published literature. Results: Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for C9orf72 (95% CI (20.9 to 53.2)), 54% for SOD1 (95% CI (32.7 to 88.6)), 38% for TARDBP (95% CI (21.1 to 69.8)) and 19% for FUS (95% CI (13.0 to 28.4)). Conclusion: Population-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.
Dementia, Genetic Predisposition to Disease, Genetics, Population, Motor Neuron Disease
Douglas, Andrew
2c789ec4-a222-43bc-a040-522ca64fea42
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Douglas, Andrew
2c789ec4-a222-43bc-a040-522ca64fea42
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Douglas, Andrew and Baralle, Diana
(2023)
Reduced penetrance of gene variants causing amyotrophic lateral sclerosis.
Journal of Medical Genetics, [jmg-2023-109580].
(doi:10.1136/jmg-2023-109580).
Abstract
Background: Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are C9orf72, SOD1, TARDBP and FUS. Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level. Objective: We sought to determine the population-level penetrance of pathogenic and likely pathogenic variants in genes commonly causing amyotrophic lateral sclerosis. Methods: Published 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 for C9orf72 were obtained from the published literature. Results: Maximum population penetrance for either amyotrophic lateral sclerosis or frontotemporal dementia was found to be 33% for C9orf72 (95% CI (20.9 to 53.2)), 54% for SOD1 (95% CI (32.7 to 88.6)), 38% for TARDBP (95% CI (21.1 to 69.8)) and 19% for FUS (95% CI (13.0 to 28.4)). Conclusion: Population-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.
Text
jmg-2023-109580.R1_Proof_hi
- Accepted Manuscript
More information
Accepted/In Press date: 5 November 2023
e-pub ahead of print date: 16 December 2023
Additional Information:
Funding Information:
This research has been funded by a National Institute for Health Research (NIHR) Research Professorship awarded to DB (RP-2016-07-011).
Publisher Copyright:
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
Keywords:
Dementia, Genetic Predisposition to Disease, Genetics, Population, Motor Neuron Disease
Identifiers
Local EPrints ID: 483988
URI: http://eprints.soton.ac.uk/id/eprint/483988
ISSN: 0022-2593
PURE UUID: 8d906664-5981-48bc-9b5f-83080d1825b7
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Date deposited: 08 Nov 2023 18:16
Last modified: 18 Mar 2024 03:16
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