{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T12:40:11Z","timestamp":1775306411766,"version":"3.50.1"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T00:00:00Z","timestamp":1577404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole\u2010exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>PDLIM5<\/jats:italic> was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating <jats:italic>TTN<\/jats:italic>\u2010variant. The <jats:italic>PDLIM5<\/jats:italic> loss\u2010of\u2010function (LoF) variant affected all cardiac\u2010specific isoforms of <jats:italic>PDLIM5<\/jats:italic> and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of <jats:italic>PDLIM5<\/jats:italic> and its direct interactors (<jats:italic>MYOT<\/jats:italic>, <jats:italic>LDB3<\/jats:italic>, and <jats:italic>MYOZ2<\/jats:italic>) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The <jats:italic>PDLIM5<\/jats:italic> variant cosegregated with the <jats:italic>TTN<\/jats:italic>\u2010variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10\u00a0kb\u2010deletion of exon 2 in <jats:italic>PDLIM5<\/jats:italic> resulting in early\u2010onset cardiac disease, showing the importance of <jats:italic>PDLIM5<\/jats:italic> in cardiac function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Heterozygous <jats:italic>PDLIM5<\/jats:italic> variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early\u2010onset cardiac disease. Other environmental and\/or genetic factors are probably necessary to unveil the cardiac phenotype in <jats:italic>PDLIM5<\/jats:italic> mutation carriers.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1049","type":"journal-article","created":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T12:45:43Z","timestamp":1577450743000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mutations in <i>PDLIM5<\/i> are rare in dilated cardiomyopathy but are emerging as potential disease modifiers"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5549-1298","authenticated-orcid":false,"given":"Job A. J.","family":"Verdonschot","sequence":"first","affiliation":[{"name":"Department of Cardiology Maastricht University Medical Centre Maastricht The Netherlands"},{"name":"Department of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4866-731X","authenticated-orcid":false,"given":"Emma L.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Cardiology Maastricht University Medical Centre Maastricht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiely N.","family":"James","sequence":"additional","affiliation":[{"name":"Rady Children's Institute for Genomic Medicine San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed W.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Sanford Children's Hospital Fargo ND USA"},{"name":"North Dakota University Fargo ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Godelieve R. F.","family":"Claes","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kari","family":"Casas","sequence":"additional","affiliation":[{"name":"Sanford Children's Hospital Fargo ND USA"},{"name":"North Dakota University Fargo ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Els K.","family":"Vanhoutte","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark R.","family":"Hazebroek","sequence":"additional","affiliation":[{"name":"Department of Cardiology Maastricht University Medical Centre Maastricht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Kringlen","sequence":"additional","affiliation":[{"name":"Sanford Children's Hospital Fargo ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele M.","family":"Pasierb","sequence":"additional","affiliation":[{"name":"Sanford Children's Hospital Fargo ND USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur","family":"van den Wijngaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan F. 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