{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T06:47:24Z","timestamp":1762066044348,"version":"build-2065373602"},"reference-count":180,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T00:00:00Z","timestamp":1663200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Vlinderkind","award":["RGY 0071\/2014","715732"],"award-info":[{"award-number":["RGY 0071\/2014","715732"]}]},{"DOI":"10.13039\/100004412","name":"Human Frontier Science Program","doi-asserted-by":"publisher","award":["RGY 0071\/2014","715732"],"award-info":[{"award-number":["RGY 0071\/2014","715732"]}],"id":[{"id":"10.13039\/100004412","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Research Counsel","award":["RGY 0071\/2014","715732"],"award-info":[{"award-number":["RGY 0071\/2014","715732"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic variants in gene-encoding proteins involved in cell\u2013cell 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\u2013phenotype 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 (&gt;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\u2013phenotype correlations, we separate variants into \u2018protein reducing\u2019 or \u2018altered protein\u2019 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.<\/jats:p>","DOI":"10.3390\/ijms231810765","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T22:11:10Z","timestamp":1663279870000},"page":"10765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Towards a Better Understanding of Genotype\u2013Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction"],"prefix":"10.3390","volume":"23","author":[{"given":"Mathilde C. S. C.","family":"Vermeer","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-2783","authenticated-orcid":false,"given":"Daniela","family":"Andrei","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Marsili","sequence":"additional","affiliation":[{"name":"Clinique de G\u00e9n\u00e9tique, H\u00f4pital Jeanne de Flandre, CHU de Lille, 59000 Lille, France"},{"name":"Department of Genetics, University Medical Center Utrecht, Utrecht University, 3508 AB Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Peter","family":"van Tintelen","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Utrecht, Utrecht University, 3508 AB Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3292-6302","authenticated-orcid":false,"given":"Herman H. W.","family":"Sillj\u00e9","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1493-2998","authenticated-orcid":false,"given":"Maarten P.","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-9363","authenticated-orcid":false,"given":"Maria C.","family":"Bolling","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1093\/hmg\/9.18.2761","article-title":"Recessive Mutation in Desmoplakin Disrupts Desmoplakin-Intermediate Filament Interactions and Causes Dilated Cardiomyopathy, Woolly Hair and Keratoderma","volume":"9","author":"Norgett","year":"2000","journal-title":"Hum. 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