Titin-truncating mutations in dilated cardiomyopathy: the long and short of it

Truncating variants in the TTN gene (TTNtv) are frequently identified in patients with dilated cardiomyopathy (DCM) but are also present in apparently healthy people in the general population. Consequently, there is considerable uncertainty about what it means for any single individual if a TTNtv is found. The aim of this review is to summarize current evidence implicating TTNtv in DCM pathogenesis and to provide some interpretative guidelines for clinical management.

Next-generation sequencing studies have recently demonstrated that TTNtv are present in approximately one in five patients with DCM but also in up to 3% of individuals in the general population. These observations question whether TTNtv are sufficient alone to cause DCM and whether some TTNtv may be more deleterious than others. It has been suggested that functional effects of TTNtv can be predicted by their location in the titin protein, with DCM-associated variants typically occurring in the A-band region and/or in exons that are highly utilized across the range of titin isoforms. Recent data from animal and cell models suggest that developmental defects in the structural assembly of titin-deficient sarcomeres provide a template for mechanical stress-induced myocardial dysfunction during later life.

Not all TTNtv are equal, and variants in constitutively expressed exons have the greatest likelihood of pathogenicity. The clinical significance of high-impact TTNtv is likely to differ according to patient context and each individual's unique suite of background genetic factors, comorbidities, and lifestyle factors. TTNtv identified in patients with DCM can be expected to have a major role in disease pathogenesis, but whether unaffected individuals with TTNtv will develop DCM is less certain.