Background: Truncating variants in TTN (TTNtv) are the leading genetic cause of dilated cardiomyopathy (DCM), an autosomal dominant condition affecting 1:250 persons with variable and age-related penetrance. Emerging evidence supports both haploinsufficiency and dominant negative pathomechanisms of TTNtv in the heart. Although skeletal muscle titinopathies are widely believed to result from a recessive mechanism of disease, we and others have identified a mild but progressive muscular dystrophy, frequently with DCM, in some individuals with monoallelic TTNtv.
Objective: In order to investigate genotype-phenotype correlations and mechanism of disease in TTNtv, we studied the premature truncation codon locations of TTNtv identified in cardioskeletal (CS) cases (n=14) and in a large DCM cohort (n=904).
Results: The majority of TTNtv in CS cases (8/13, 61.5%) localized to the large A-band exon 326, compared to 205/895 (22.9%) of DCM cases, and 101/957 (10.5%) of gnomad cases (exon 326 constitutive coding length = 21.3%). The remainder of exon 326 TTNtv in CS cases localized to the distal A band. We hypothesized that TTNtv in exon 326 may be more penetrant in skeletal muscle compared to other TTNtv due to decreased nonsense-mediated decay efficiency, which is more likely to occur at the 5’ region of exon 326 due to its very large size (17,106bp). The mean premature truncation codon to downstream exon junction complex distance in exon 326 TTNtv was 10,473 bp in CS cases (n=8), 7,708 bp in DCM cases (n=205), and 7,856 in gnomAD controls (n=101).
Conclusions: In addition to potentially impacting nonsense mediated decay efficiency, exon 326 and other A-band TTNtv may alter the binding of myosin and MyBPC-3, contributing to sarcomeric and cytoskeletal dysfunction. Further study is needed to rigorously investigate the observed trends and elucidate the mechanisms by which TTNtv impact both cardiac and skeletal muscle tissue.