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Challenges in clinicogenetic correlations: One gene – many phenotypes unravelling the basis of phenotypic heterogeneity in monogenic disorders

Magrinelli, F; Balint, B; Bhatia, KP; (2021) Challenges in clinicogenetic correlations: One gene – many phenotypes unravelling the basis of phenotypic heterogeneity in monogenic disorders. Movement Disorders Clinical Practice (mdc3.131) 10.1002/mdc3.13165. (In press). Green open access

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Abstract

Background: Progress in genetics – particularly the advent of next‐generation sequencing (NGS) – has enabled an unparalleled gene discovery and revealed unmatched complexity of genotype–phenotype correlations in movement disorders. Among other things, it has emerged that mutations in one and the same gene can cause multiple, often markedly different phenotypes. Consequently, movement disorder specialists have increasingly experienced challenges in clinicogenetic correlations. Objectives: To deconstruct biological phenomena and mechanistic bases of phenotypic heterogeneity in monogenic movement disorders and neurodegenerative diseases. To discuss the evolving role of movement disorder specialists in reshaping disease phenotypes in the NGS era. Methods: This scoping review details phenomena contributing to phenotypic heterogeneity and their underlying mechanisms. Results: Three phenomena contribute to phenotypic heterogeneity, namely incomplete penetrance, variable expressivity and pleiotropy. Their underlying mechanisms, which are often shared across phenomena and non‐mutually exclusive, are not fully elucidated. They involve genetic factors (ie, different mutation types, dynamic mutations, somatic mosaicism, intragenic intra‐ and inter‐allelic interactions, modifiers and epistatic genes, mitochondrial heteroplasmy), epigenetic factors (ie, genomic imprinting, X‐chromosome inactivation, modulation of genetic and chromosomal defects), and environmental factors. Conclusion: Movement disorders is unique in its reliance on clinical judgment to accurately define disease phenotypes. This has been reaffirmed by the NGS revolution, which provides ever‐growing sequencing data and fuels challenges in variant pathogenicity assertions for such clinically heterogeneous disorders. Deep phenotyping, with characterization and continual updating of “core” phenotypes, and comprehension of determinants of genotype–phenotype complex relationships are crucial for clinicogenetic correlations and have implications for the diagnosis, treatment and counseling.

Type: Article
Title: Challenges in clinicogenetic correlations: One gene – many phenotypes unravelling the basis of phenotypic heterogeneity in monogenic disorders
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/mdc3.13165
Publisher version: http://dx.doi.org/10.1002/mdc3.13165
Language: English
Additional information: © 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: clinicogenetic correlation, genotype movement disorders, phenotype phenotypic heterogeneity
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10122928
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