{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:17:37Z","timestamp":1785453457880,"version":"3.56.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Nonischemic cardiomyopathies are frequently caused by genetic mutations in about 100 different genes. The cardiomyopathy-associated gene\n              <jats:italic toggle=\"yes\">DES<\/jats:italic>\n              encodes the intermediate filament protein desmin, which is important for the structural integrity of the cardiomyocytes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Using a next-generation sequencing approach, we performed cascade screening of a previously identified heterozygous\n              <jats:italic toggle=\"yes\">DES<\/jats:italic>\n              missense mutation (c.380G&gt;C, p.R127P) segregating in a large 6-generation Kuwaiti family, where several members died from sudden cardiac death or developed different cardiomyopathies, partially in combination with conduction disease and atrial fibrillation.\n              <jats:italic toggle=\"yes\">DES<\/jats:italic>\n              -p.R127P affects a highly conserved position and is absent or super rare in different genetic human population databases. In silico predictions support the pathogenicity of\n              <jats:italic toggle=\"yes\">DES<\/jats:italic>\n              -p.R127P. To investigate the detrimental impact of desmin-p.R127P, we performed cell transfection experiments using different cell lines and cardiomyocytes derived from induced pluripotent stem cells in combination with confocal microscopy.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>These experiments demonstrated a severe desmin filament assembly defect leading to aberrant cytoplasmic desmin aggregates, even when co-expressed with wild-type desmin. Atomic force microscopy analysis supported the filament assembly defect of mutant recombinant desmin-p.R127P. To investigate the physicochemical impact of the amino acid at this position, we generated a set of 20 different variants and analyzed their filament formation in cell culture. Most of these variants disturbed the filament assembly comparable to p.R127P.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              In summary, we present and characterize a likely pathogenic missense mutation\n              <jats:italic toggle=\"yes\">DES<\/jats:italic>\n              -p.R127P, which causes high cardiac mortality and morbidity in the described family. Our study has relevance for the interpretation and classification of further\n              <jats:italic toggle=\"yes\">DES<\/jats:italic>\n              variants and might be helpful for the genetic counseling of patients and their relatives in future cases.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.124.004896","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T05:00:17Z","timestamp":1745384417000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Phenotypic Diversity Caused by the\n            <i>DES<\/i>\n            Missense Mutation p.R127P (c.380G&gt;C) Contributing to Significant Cardiac Mortality and Morbidity Associated With a Desmin Filament Assembly Defect"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-5193","authenticated-orcid":true,"given":"Mohammad A.","family":"Ebrahim","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Kuwait University Faculty of Medicine, Affiliated with Chest Diseases Hospital, Jabriya (M.A.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7824-5169","authenticated-orcid":true,"given":"Naser M.","family":"Ali","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat (N.M.A., B.Y.A.)."},{"name":"Department of Medical Laboratories, General Ahmadi Hospital (KOC Hospital), Kuwait (N.M.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buthaina Y.","family":"Albash","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat (N.M.A., B.Y.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali H.","family":"Al Sayegh","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Chest Diseases Hospital, Ministry of Health, Kuwait City (A.H.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3940-418X","authenticated-orcid":true,"given":"Noof B.","family":"Ahmad","sequence":"additional","affiliation":[{"name":"FFR RCSI, Dublin, Level II Qualified CMR Reader by SCMR, Consultant Diagnostic Imaging Chest Disease Hospital, Kuwait (N.B.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6852-634X","authenticated-orcid":true,"given":"Sabrina","family":"Vo\u00df","sequence":"additional","affiliation":[{"name":"Erich &amp; Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Medical School OWL (University of Bielefeld), Bad Oeynhausen, Germany (S.V., J.G., S.H., H.M., A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8015-7794","authenticated-orcid":true,"given":"Franziska","family":"Klag","sequence":"additional","affiliation":[{"name":"Department of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld University, Germany (F.K., V.W., D.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3347-9888","authenticated-orcid":true,"given":"Joline","family":"Gro\u00df","sequence":"additional","affiliation":[{"name":"Erich &amp; Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Medical School OWL (University of Bielefeld), Bad Oeynhausen, Germany (S.V., J.G., S.H., H.M., 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