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Intricacies of aetiology in intrafamilial degenerative disease

The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the disease trait in affected, but not unaffected, individuals. However, instances of intrafamilial etiological heterogeneity, where pathogen...

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Autores principales: Lowry, Jessica L, Ryan, Éanna B, Esengul, Y Taylan, Siddique, Nailah, Siddique, Teepu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585693/
https://www.ncbi.nlm.nih.gov/pubmed/33134917
http://dx.doi.org/10.1093/braincomms/fcaa120
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author Lowry, Jessica L
Ryan, Éanna B
Esengul, Y Taylan
Siddique, Nailah
Siddique, Teepu
author_facet Lowry, Jessica L
Ryan, Éanna B
Esengul, Y Taylan
Siddique, Nailah
Siddique, Teepu
author_sort Lowry, Jessica L
collection PubMed
description The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the disease trait in affected, but not unaffected, individuals. However, instances of intrafamilial etiological heterogeneity, where pathogenic variants in a culprit gene are not shared among all affected family members, continue to emerge and confound gene-discovery and genetic counselling efforts. Discordant intrafamilial cases lacking a mutation shared by other affected family members are described as disease phenocopies. This description often results in an over-simplified acceptance of an environmental cause of disease in the phenocopy cases, while the role of intrafamilial genetic heterogeneity, shared de novo mutations or epigenetic aberrations in such families is often ignored. On a related note, it is now evident that the same disease-associated variant can be present in individuals exhibiting clinically distinct phenotypes, thereby genetically uniting seemingly unrelated syndromes to form a spectrum of disease. Herein, we discuss the intricacies of determining complex degenerative disease aetiology and suggest alternative mechanisms of disease transmission that may account for the apparent missing heritability of disease.
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spelling pubmed-75856932020-10-29 Intricacies of aetiology in intrafamilial degenerative disease Lowry, Jessica L Ryan, Éanna B Esengul, Y Taylan Siddique, Nailah Siddique, Teepu Brain Commun Review Article The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the disease trait in affected, but not unaffected, individuals. However, instances of intrafamilial etiological heterogeneity, where pathogenic variants in a culprit gene are not shared among all affected family members, continue to emerge and confound gene-discovery and genetic counselling efforts. Discordant intrafamilial cases lacking a mutation shared by other affected family members are described as disease phenocopies. This description often results in an over-simplified acceptance of an environmental cause of disease in the phenocopy cases, while the role of intrafamilial genetic heterogeneity, shared de novo mutations or epigenetic aberrations in such families is often ignored. On a related note, it is now evident that the same disease-associated variant can be present in individuals exhibiting clinically distinct phenotypes, thereby genetically uniting seemingly unrelated syndromes to form a spectrum of disease. Herein, we discuss the intricacies of determining complex degenerative disease aetiology and suggest alternative mechanisms of disease transmission that may account for the apparent missing heritability of disease. Oxford University Press 2020-10-06 /pmc/articles/PMC7585693/ /pubmed/33134917 http://dx.doi.org/10.1093/braincomms/fcaa120 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Review Article
Lowry, Jessica L
Ryan, Éanna B
Esengul, Y Taylan
Siddique, Nailah
Siddique, Teepu
Intricacies of aetiology in intrafamilial degenerative disease
title Intricacies of aetiology in intrafamilial degenerative disease
title_full Intricacies of aetiology in intrafamilial degenerative disease
title_fullStr Intricacies of aetiology in intrafamilial degenerative disease
title_full_unstemmed Intricacies of aetiology in intrafamilial degenerative disease
title_short Intricacies of aetiology in intrafamilial degenerative disease
title_sort intricacies of aetiology in intrafamilial degenerative disease
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585693/
https://www.ncbi.nlm.nih.gov/pubmed/33134917
http://dx.doi.org/10.1093/braincomms/fcaa120
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