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  • Review Article
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Mechanisms underlying phenotypic variation in neurogenetic disorders

Nature Reviews Neurology volume 19, pages 363–370 (2023)Cite this article

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Abstract

Neurological diseases associated with pathogenic variants in a specific gene, or even with a specific pathogenic variant, can show profound phenotypic variation with regard to symptom presentation, age at onset and disease course. Highlighting examples from a range of neurogenetic disorders, this Review explores emerging mechanisms that are involved in this variability, including environmental, genetic and epigenetic factors that influence the expressivity and penetrance of pathogenic variants. Environmental factors, some of which can potentially be modified to prevent disease, include trauma, stress and metabolic changes. Dynamic patterns of pathogenic variants might explain some of the phenotypic variations, for example, in the case of disorders caused by DNA repeat expansions such as Huntington disease (HD). An important role for modifier genes has also been identified in some neurogenetic disorders, including HD, spinocerebellar ataxia and X-linked dystonia–parkinsonism. In other disorders, such as spastic paraplegia, the basis for most of the phenotypic variability remains unclear. Epigenetic factors have been implicated in disorders such as SGCE-related myoclonus–dystonia and HD. Knowledge of the mechanisms underlying phenotypic variation is already starting to influence management strategies and clinical trials for neurogenetic disorders.

Key points

  • Studies in large data sets are providing important insights into the correlations between pathogenic gene variation and clinical phenotypes in people with neurogenetic disorders.

  • These analyses have shown that different genetic variants can give rise to similar phenotypes and, conversely, a single pathogenic variant might be associated with multiple phenotypes.

  • The mechanisms underlying phenotypic variations in neurogenetic disorders are beginning to be elucidated.

  • Environmental factors, sometimes interacting with genetic factors, can increase or reduce the risk of disease.

  • Genetic factors that are known to modify phenotypes include mechanisms intrinsic to the pathogenic variant, such as dynamic mutations, and modifier genes that influence the function of proteins encoded by pathogenic variants.

  • Epigenetic factors, such as DNA methylation, chromatin remodelling, histone modifications and non-coding RNAs, might help to explain diverse presentations among family members with the same pathogenic variant.

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    Jean-Marc Burgunder

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Burgunder, JM. Mechanisms underlying phenotypic variation in neurogenetic disorders. Nat Rev Neurol 19, 363–370 (2023). https://doi.org/10.1038/s41582-023-00811-4

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