July 27, 2023

Biallelic Truncating Variants in Children with Titinopathy Represent a Recognizable Condition with Distinctive Muscular and Cardiac Characteristics: A Report on Five Patients

Anwar Baban, Marianna Cicenia, Monia Magliozzi, Giovanni Parlapiano, Marco Cirillo, Giulia Pascolini, Fabiana Fattori, Maria Gnazzo, Pasqualina Bruno, Lorenzo De Luca, Luca Di Chiara, Paola Francalanci, Bjarne Udd, Aurelio Secinaro, Antonio Amodeo, Enrico Silvio Bertini, Marco Savarese, Fabrizio Drago, Antonio Novelli

The largest protein, titin, is encoded by the 363 exons of the TTN gene on chromosome 2q31. It has a length of 27,000-33,000 amino acids and four regions: an N-terminal Z-disc, an I-band, an A-band, and a C-terminal M-line. TTN variants cause skeletal/myocardial disorders. These conditions can have various presentations depending upon the TTN variants zygosity, age, severity, muscles affected. Genotype-phenotype links exist, e.g., exon 364/344 variants are reported in muscular dystrophy/myopathy, respectively. Mutations in 100 genes cause dilated cardiomyopathies, with variable expression levels. Biallelic TTN truncation variants (TTNtv) increase the risk of heart defects. TTNtv monoallelic variants are related to myopathy/cardiomyopathy and late-onset dilated cardiomyopathy (DCM). This study details cardiac involvement in pediatric titinopathy through diagnostic assessments and histopathology in 5 patients with biallelic TTN variants. 


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The authors carried out a retrospective study. The medical histories of pediatric patients with compound heterozygous TTN changes and cardiac disorders were examined. The study follows ethical guidelines and includes demographics, family history, cardiac assessments, genetic testing, and diagnostic tests from patients. Next-generation sequencing was implemented in genetic testing. Geneyx Analysis was used to annotate variants. The TGex-Geneyx analysis tool was applied to assess and filter variants related to the 129 cardiomyopathy (CMP) genes. This investigation focuses on genetic variants and cardiac imaging techniques such as MRI and CMR. It also includes a comprehensive list of CMP-related genes. On cardiac specimens, histology and immunohistochemistry were carried out. 



Patients had congenital heart defects, dilated cardiomyopathy, and arrhythmias as prominent cardiac manifestations. Most patients had major arthrogryposis multiplex and muscular abnormalities, with some having developmental delays and dysmorphic features. TTN variants that met pathogenic or likely pathogenic criteria were identified in each patient. These findings help to clarify the various clinical aspects of this condition in pediatric patients. 


This paper highlights the importance of biallelic TTNtv in causing congenital myopathy with associated cardiac manifestations, illustrating the importance of a thorough evaluation. The study emphasizes that, while muscular and skeletal involvement is well-documented, pediatric cardiac presentations are less researched. The structural regions of the TTN protein and the impact of different TTN variants on the heterogeneous phenotypes are also discussed. The authors concluded that biallelic TTNtv could cause severe and early-onset DCM, with compound heterozygous cases often exhibiting a more severe and earlier phenotype. 


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