{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T13:42:17Z","timestamp":1777642937026,"version":"3.51.4"},"reference-count":33,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T00:00:00Z","timestamp":1597881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Variants in <jats:italic>TTN<\/jats:italic> are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of <jats:italic>TTN<\/jats:italic> variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of <jats:italic>TTN<\/jats:italic> variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A\u2010band <jats:italic>TTN<\/jats:italic> variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous <jats:italic>TTN<\/jats:italic> variants. Recent reports show pathogenic variants in <jats:italic>TTN<\/jats:italic> may result in a broader phenotypic spectrum than previously recognized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated <jats:italic>TTN<\/jats:italic> genotype\u2010phenotype correlations in probands with skeletal myopathy and\/or cardiomyopathy. Probands with <jats:italic>TTN<\/jats:italic> truncating variants (<jats:italic>TTN<\/jats:italic>tv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Forty\u2010nine probands were identified with <jats:italic>TTN<\/jats:italic>tv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n\u00a0=\u00a030), skeletal muscle (n\u00a0=\u00a012), or both (cardioskeletal, n\u00a0=\u00a07). Within the cardioskeletal group, 5\/7 probands had heterozygous <jats:italic>TTN<\/jats:italic>tv predicted to affect the distal (3\u2019) end of the A\u2010band. All cardioskeletal probands had onset of proximal\u2010predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Although heterozygous <jats:italic>TTN<\/jats:italic>tv in the A\u2010band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb\u2010girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A\u2010band <jats:italic>TTN<\/jats:italic>tv who may be at risk for multisystem disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1460","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T05:43:29Z","timestamp":1598593409000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Novel heterozygous truncating titin variants affecting the A\u2010band are associated with cardiomyopathy and myopathy\/muscular dystrophy"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0027-0313","authenticated-orcid":false,"given":"Kelly A.","family":"Rich","sequence":"first","affiliation":[{"name":"The Ohio State University Wexner Medical Center The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tia","family":"Moscarello","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease Stanford University Stanford CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carly","family":"Siskind","sequence":"additional","affiliation":[{"name":"Stanford Health Care Stanford University Stanford CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy","family":"Brock","sequence":"additional","affiliation":[{"name":"The Ohio State University Center for Biostatistics The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher A.","family":"Tan","sequence":"additional","affiliation":[{"name":"Invitae Corporation San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Vatta","sequence":"additional","affiliation":[{"name":"Invitae Corporation San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas L.","family":"Winder","sequence":"additional","affiliation":[{"name":"Invitae Corporation San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bakri","family":"Elsheikh","sequence":"additional","affiliation":[{"name":"The Ohio State University Wexner Medical Center The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah","family":"Vicini","sequence":"additional","affiliation":[{"name":"The Ohio State University Wexner Medical Center The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brianna","family":"Tucker","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease Stanford University Stanford CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilly","family":"Palettas","sequence":"additional","affiliation":[{"name":"The Ohio State University Center for Biostatistics The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ray E.","family":"Hershberger","sequence":"additional","affiliation":[{"name":"The Ohio State University Wexner Medical Center The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John T.","family":"Kissel","sequence":"additional","affiliation":[{"name":"The Ohio State University Wexner Medical Center The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Morales","sequence":"additional","affiliation":[{"name":"The Ohio State University Wexner Medical Center The Ohio State University Columbus OH USA"},{"name":"Invitae Corporation San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6583-9996","authenticated-orcid":false,"given":"Jennifer","family":"Roggenbuck","sequence":"additional","affiliation":[{"name":"The Ohio State University Wexner Medical Center The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,8,20]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Online Mendelian inheritance in man OMIM\u00ae.Baltimore MD:McKusick\u2010Nathans Institute of Genetic Medicine Johns Hopkins University;2020. 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