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Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction

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 arrhyt...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9503274/
https://www.ncbi.nlm.nih.gov/pubmed/36142674
http://dx.doi.org/10.3390/ijms231810765
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author 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.
author_facet 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.
author_sort Vermeer, Mathilde C. S. C.
collection PubMed
description 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 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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spelling pubmed-95032742022-09-24 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. Int J Mol Sci Review 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 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. MDPI 2022-09-15 /pmc/articles/PMC9503274/ /pubmed/36142674 http://dx.doi.org/10.3390/ijms231810765 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
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.
Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction
title Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction
title_full Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction
title_fullStr Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction
title_full_unstemmed Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction
title_short Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction
title_sort towards a better understanding of genotype–phenotype correlations and therapeutic targets for cardiocutaneous genes: the importance of functional studies above prediction
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9503274/
https://www.ncbi.nlm.nih.gov/pubmed/36142674
http://dx.doi.org/10.3390/ijms231810765
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