{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T19:52:39Z","timestamp":1785268359140,"version":"3.55.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005633","name":"Syd\u00e4ntutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010133","name":"Aarne Koskelon S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010133","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Special Governmental Subsidy (EVO) grant"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (<jats:italic>NRAP<\/jats:italic>) were identified in a few patients with sporadic DCM.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and results<\/jats:title>\n<jats:p>We determined the frequency of rare <jats:italic>NRAP<\/jats:italic> variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) <jats:italic>NRAP<\/jats:italic> variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic <jats:italic>NRAP<\/jats:italic> variants were enriched in DCM vs. controls (OR 1052, p&lt;0.0001). Based on the frequency of <jats:italic>NRAP<\/jats:italic> PTVs in the gnomAD reference population, and predicting full penetrance, biallelic <jats:italic>NRAP<\/jats:italic> variants could explain 0.25%-2.46% of all DCM cases.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Loss-of-function in <jats:italic>NRAP<\/jats:italic> is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0245681","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T18:47:58Z","timestamp":1612378078000},"page":"e0245681","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2306-2883","authenticated-orcid":true,"given":"Juha W.","family":"Koskenvuo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inka","family":"Saarinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saija","family":"Ahonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Tommiska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sini","family":"Weckstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eija 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of the cardiomyopathies: A position statement from the european society of cardiology working group on myocardial and pericardial diseases","volume":"29","author":"P Elliott","year":"2008","journal-title":"Eur Heart J"},{"key":"pone.0245681.ref002","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1161\/01.CIR.80.3.564","article-title":"Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. 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