Biallelic truncating variants in children with titinopathy represent a recognizable condition with distinctive muscular and cardiac characteristics: a report on five patients

Frontiers in Cardiovascular Medicine

Cardiovascular Medicine

Aurelio Secinaro¹  Pasqualina Bruno²  Marco Cirillo³  Paola Francalanci⁴  Marco Savarese⁵  Bjarne Udd⁶  Antonio Amodeo⁷  Antonio Novelli⁸  Monia Magliozzi⁸  Luca Di Chiara⁹  Fabrizio Drago^1,10  Anwar Baban^1,10  Marianna Cicenia^1,10  Lorenzo De Luca^1,10  Giovanni Parlapiano^1,11  Giulia Pascolini^1,11  Maria Gnazzo^1,12  Fabiana Fattori^1,13  Enrico Silvio Bertini^1,13 

[1] Advanced Cardiothoracic Imaging Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Department of Cardiac Surgery, Cardiology, Heart and Lung Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Department of Imaging, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Department of Pathology, Bambino Gesù Children’s Hospital and Research Institute, IRCCS, Rome, Italy;Folkhälsan Research Center, Helsinki, Finland;Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland;Folkhälsan Research Center, Helsinki, Finland;Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland;Department of Neurology, Vaasa Central Hospital, Vaasa, Finland;Heart Failure, and Transplant, Mechanical Circulatory Support Complex Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Pediatric Cardiac Intensive Care Unit, Department of Cardiology and Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Pediatric Cardiology and Arrhythmia/Syncope Complex Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Pediatric Cardiology and Arrhythmia/Syncope Complex Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, Rome, Italy;Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;

关键词: titinopathy;    TTN;    truncating variant;    dilated cardiomyopathy;    neuromuscular disease;    heart failure;    children;   

DOI  :  10.3389/fcvm.2023.1210378

 received in 2023-04-22, accepted in 2023-07-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundMonoallelic and biallelic TTN truncating variants (TTNtv) may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous TTNtv is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children.MethodsWe reviewed the medical records of pediatric patients with biallelic TTNtv and cardiac involvement. Clinical exome sequencing excluded pathogenic/likely pathogenic variants in major CMP genes.ResultsFive pediatric patients (four male) with biallelic TTNtv 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, n = 3) and left ventricular non-compaction (n = 1) 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, n = 2; non-sustained ventricular tachycardia, n = 2) and nocturnal first-degree atrio-ventricular block (n = 2). 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.ConclusionBiallelic TTNtv 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.

【 授权许可】

Unknown   
© 2023 Baban, Cicenia, Magliozzi, Parlapiano, Cirillo, Pascolini, Fattori, Gnazzo, Bruno, De Luca, Di Chiara, Francalanci, Udd, Secinaro, Amodeo, Bertini, Savarese, Drago and Novelli.