Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction
Vermeer, Mathilde C S C; Andrei, Daniela; Marsili, Luisa; van Tintelen, J Peter; Silljé, Herman H W; van den Berg, Maarten P; van der Meer, Peter; Bolling, Maria C
(2022) International journal of molecular sciences, volume 23, issue 18
(Article)
Abstract
Genetic variants in gene-encoding proteins involved in cell–cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair
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abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype–phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype–phenotype correlations, we separate variants into ‘protein reducing’ or ‘altered protein’ variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation.
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Keywords: Cardiomyopathies/genetics, Genetic Association Studies, Humans, Mutation, Phenotype, Skin Abnormalities, genotype–phenotype correlation, functional analysis of genetic variants, cardiocutaneous syndromes, Molecular Biology, Spectroscopy, Catalysis, Inorganic Chemistry, Computer Science Applications, Physical and Theoretical Chemistry, Organic Chemistry, Review, Journal Article
ISSN: 1422-0067
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: Funding Information: This work was supported by Vlinderkind (grant number: none, due to patient organization funding to M.C.B.], the Human Frontier Science Program (grant number RGY 0071/2014 to P.v.d.M.) and the European Research Counsel (STOP-HF (StG); grant number 715732, ERC-2016-STG to P.v.d.M.). Publisher Copyright: © 2022 by the authors.
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