{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T10:21:56Z","timestamp":1786270916033,"version":"build-2736575974"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Monoallelic and biallelic <jats:italic>TTN<\/jats:italic> truncating variants (<jats:italic>TTNtv<\/jats:italic>) may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous <jats:italic>TTNtv<\/jats:italic> is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We reviewed the medical records of pediatric patients with biallelic <jats:italic>TTNtv<\/jats:italic> and cardiac involvement. Clinical exome sequencing excluded pathogenic\/likely pathogenic variants in major CMP genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Five pediatric patients (four male) with biallelic <jats:italic>TTNtv<\/jats:italic> were included. Major arthrogryposis multiplex was observed in four patients; no patient showed intellectual disability. At a cardiac level, congenital heart defects (atrial and ventricular septal defects, <jats:italic>n<\/jats:italic>\u2009=\u20093) and left ventricular non-compaction (<jats:italic>n<\/jats:italic>\u2009=\u20091) were reported. All patients had dilated cardiomyopathy (DCM) diagnosed at birth in one patient and at the age of 10, 13, 14, and 17 years in the other four patients. Heart rhythm monitoring showed tachyarrhythmias (premature ventricular contractions, <jats:italic>n<\/jats:italic>\u2009=\u20092; non-sustained ventricular tachycardia, <jats:italic>n<\/jats:italic>\u2009=\u20092) and nocturnal first-degree atrio-ventricular block (<jats:italic>n<\/jats:italic>\u2009=\u20092). Cardiac magnetic resonance (CMR) imaging was performed in all patients and revealed a peculiar late gadolinium enhancement distribution in three patients. HyperCKemia was present in two patients and end-stage heart failure in four. End-organ damage requiring heart transplantation (HT) was indicated in two patients, who were operated on successfully.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Biallelic <jats:italic>TTNtv<\/jats:italic> should be considered when evaluating children with severe and early-onset DCM, particularly if skeletal and muscular abnormalities are present, e.g., arthrogryposis multiplex and congenital progressive myopathy. End-stage heart failure is common and may require HT.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2023.1210378","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T23:34:06Z","timestamp":1690500846000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Biallelic truncating variants in children with titinopathy represent a recognizable condition with distinctive muscular and cardiac characteristics: a report on five patients"],"prefix":"10.3389","volume":"10","author":[{"given":"Anwar","family":"Baban","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Cicenia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Magliozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Parlapiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Cirillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Pascolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Fattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gnazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasqualina","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"De Luca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Di Chiara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Francalanci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjarne","family":"Udd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelio","family":"Secinaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Amodeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico Silvio","family":"Bertini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Savarese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Drago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1161\/01.res.86.11.1114","article-title":"Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity","volume":"86","author":"Freiburg","year":"2000","journal-title":"Circ Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cca.2006.06.035","article-title":"Cardiac titin: structure, functions and role in disease","volume":"375","author":"LeWinter","year":"2007","journal-title":"Clin Chim Acta"},{"key":"B3","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1038\/ejhg.2017.16","article-title":"A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population","volume":"25","author":"Peri\u0107","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.3389\/fphys.2019.01436","article-title":"The giant protein titin's role in cardiomyopathy: genetic, transcriptional, and post-translational modifications of TTN and their contribution to cardiac disease","volume":"10","author":"Tharp","year":"2019","journal-title":"Front Physiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"eabd3079","DOI":"10.1126\/scitranslmed.abd3079","article-title":"Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to TTN mutations","volume":"13","author":"Fomin","year":"2021","journal-title":"Sci Transl Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.1038\/s41436-020-0914-2","article-title":"Genotype-phenotype correlations in recessive titinopathies","volume":"22","author":"Savarese","year":"2020","journal-title":"Genet Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/978-3-030-27371-2_2","article-title":"The genetic landscape of cardiomyopathies","author":"Gerull","year":"2019","journal-title":"Genet Causes Cardiac Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"883","DOI":"10.3390\/genes12060883","article-title":"The combined human genotype of truncating TTN and RBM20 mutations is associated with severe and early onset of dilated cardiomyopathy","volume":"12","author":"Gaertner","year":"2021","journal-title":"Genes"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e022854","DOI":"10.1161\/JAHA.121.022854","article-title":"Genotype and cardiac outcomes in pediatric dilated cardiomyopathy","volume":"11","author":"Khan","year":"2022","journal-title":"J Am Heart Ass"},{"key":"B10","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1111\/cge.13645","article-title":"Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3","volume":"96","author":"K\u00fchnisch","year":"2019","journal-title":"Clin Genet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1001\/jamacardio.2021.5890","article-title":"Association of titin variations with late-onset dilated cardiomyopathy","volume":"7","author":"Cannat\u00e0","year":"2022","journal-title":"JAMA Cardiol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e003389","DOI":"10.1161\/CIRCGEN.121.003389","article-title":"Contribution of noncanonical splice variants to TTN truncating variant cardiomyopathy","volume":"14","author":"Patel","year":"2021","journal-title":"Circ Genom Precis Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"16409","DOI":"10.1038\/s41598-019-52911-1","article-title":"Low mutation rate in the TTN gene in paediatric patients with dilated cardiomyopathy\u2014a pilot study","volume":"9","author":"Zaklyazminskaya","year":"2019","journal-title":"Sci Rep"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"Varsome: the human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1097\/GIM.0b013e31816b5cae","article-title":"ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007","volume":"10","author":"Richards","year":"2008","journal-title":"Genet Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"47","DOI":"10.3390\/jcdd9020047","article-title":"Cardiomyopathies in children and systemic disorders: when is it useful to look beyond the heart?","volume":"9","author":"Cal\u00ec","year":"2022","journal-title":"J Cardiovasc Dev Dis"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.3390\/biom11111578","article-title":"Myocardial and arrhythmic spectrum of neuromuscular disorders in children","volume":"11","author":"Baban","year":"2021","journal-title":"Biomolecules"},{"key":"B19","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s12881-019-0895-7","article-title":"Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10","volume":"20","author":"Khan","year":"2019","journal-title":"BMC Med Genet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/j.nmd.2017.06.013","article-title":"A \u2018second truncation\u2019 in TTN causes early onset recessive muscular dystrophy","volume":"27","author":"Harris","year":"2017","journal-title":"Neuromuscul Disord"},{"key":"B21","doi-asserted-by":"publisher","first-page":"eabd7287","DOI":"10.1126\/scitranslmed.abd7287","article-title":"Truncated titin proteins in dilated cardiomyopathy","volume":"13","author":"McAfee","year":"2021","journal-title":"Sci Transl Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1212\/WNL.0000000000002200","article-title":"A new titinopathy: childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy","volume":"85","author":"De Cid","year":"2015","journal-title":"Neurology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/ana.25241","article-title":"Congenital titinopathy: comprehensive characterization and pathogenic insights","volume":"83","author":"Oates","year":"2018","journal-title":"Ann Neurol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1002\/ana.21089","article-title":"C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy","volume":"61","author":"Carmignac","year":"2007","journal-title":"Ann Neurol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.hfc.2021.05.011","article-title":"Advanced heart failure in special population\u2014pediatric age","volume":"17","author":"Monda","year":"2021","journal-title":"Heart Fail Clin"},{"key":"B26","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1136\/heartjnl-2021-319682","article-title":"Dilated cardiomyopathy: the role of genetics, highlighted in a family with filamin C (FLNC) variant","volume":"108","author":"Dungu","year":"2022","journal-title":"Heart"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.1016\/j.jacc.2017.03.530","article-title":"Truncating variants in titin independently predict early arrhythmias in patients with dilated cardiomyopathy","volume":"69","author":"Tayal","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.ijcard.2022.01.008","article-title":"Arrhythmogenic cardiomyopathy in children according to \u201cPadua criteria\u201c: single pediatric center experience","volume":"350","author":"Cicenia","year":"2022","journal-title":"Int J Cardiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3390\/jcdd9040098","article-title":"Arrhythmogenic cardiomyopathy: diagnosis, evolution, risk stratification and pediatric population\u2014where are we?","volume":"9","author":"Cicenia","year":"2022","journal-title":"J Cardiovasc Dev Dis"},{"key":"B30","doi-asserted-by":"publisher","first-page":"374","DOI":"10.3389\/fped.2020.00374","article-title":"Cardiovascular involvement in pediatric laminopathies. Report of six patients and literature revision","volume":"8","author":"Baban","year":"2020","journal-title":"Front Pediatr"},{"key":"B31","doi-asserted-by":"publisher","first-page":"332","DOI":"10.3390\/jcdd9100332","article-title":"Cardiovascular involvement in pediatric FLNC variants: a case series of fourteen patients","volume":"9","author":"Baban","year":"2022","journal-title":"J Cardiovasc Dev Dis"},{"key":"B32","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.hfc.2021.07.016","article-title":"Genetics in congenital heart diseases: unraveling the link between cardiac morphogenesis, heart muscle disease, and electrical disorders","volume":"18","author":"Baban","year":"2022","journal-title":"Heart Fail Clin"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1002\/acn3.50831","article-title":"Novel TTN mutations and muscle imaging characteristics in congenital titinopathy","volume":"6","author":"Yu","year":"2019","journal-title":"Ann Clin Transl Neurol"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1210378\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T23:34:09Z","timestamp":1690500849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1210378\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,27]]},"references-count":33,"alternative-id":["10.3389\/fcvm.2023.1210378"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2023.1210378","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,27]]},"article-number":"1210378"}}