Novel heterozygous truncating titin variants affecting the A‐band are associated with cardiomyopathy and myopathy/muscular dystrophy. Issue 10 (20th August 2020)

• Record Type: Journal Article
• Authors: Rich, Kelly A.; Moscarello, Tia; Siskind, Carly; Brock, Guy; Tan, Christopher A.; Vatta, Matteo; Winder, Thomas L.; Elsheikh, Bakri; Vicini, Leah; Tucker, Brianna; Palettas, Marilly; Hershberger, Ray E.; Kissel, John T.; Morales, Ana; Roggenbuck, Jennifer
• Is Part Of: Molecular genetics & genomic medicine. Volume 8:Issue 10(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-08-20
• Subjects: dilated cardiomyopathy -- genotype‐phenotype correlation -- skeletal myopathy -- TTN -- variant interpretation; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1460
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A‐band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. Methods: Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype‐phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants ( TTN 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. Results: Forty‐nine probands were identified with TTN tv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTN tv predicted to affect the distal (3') end of the A‐band. All cardioskeletal probands had onset of proximal‐predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. Conclusion: Although heterozygous TTN tv in the A‐band 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‐girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A‐band TTN tv who may be at risk for multisystem disease. Abstract : Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. We investigated TTN genotype‐phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Although heterozygous TTN tv in the A‐band are known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb‐girdle pattern of weakness.