Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

Abstract

TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.

Role of titin in cardiomyopathy: from DNA variants to patient stratification

“…In another study, evaluation of 72 probands with DCM (17 with TTNtv) revealed no difference in the incidence of adverse cardiac events between carriers of TTNtv and noncarriers (mean follow-up 63 months) 34 , although the investigators did report a higher penetrance and poorer outcomes in male carriers of TTNtv than in female carriers 34 . Importantly, TTNtv are reported to be associated with a favourable response to treatment 79 .…”

“…The association between DCM and TTNtv has subsequently been widely replicated [27][28][29][30][31][32][33][34] {very recent addition: TAYAL et al, JACC 18:2264-2274 (2017)}, with TTNtv accounting for ~15% of DCM cases in the largest series of unselected patients 30,33 (although much more rarely identified in paediatric cardiomyopathy 28,35 ). TTN sequencing has become adopted routinely in diagnostic laboratories, markedly increasing the yield and, therefore, utility of genetic testing in DCM for confirmatory and familial screening.…”

“…Although such variants are actionable when found in a patient with known disease, this information does not indicate what proportion of family members, or unrelated individuals, who are found to have such a variant will go on to develop disease. Relatives of patients with DCM have been investigated in several studies 26,32,34,79 . Although the total number of individuals and distinct DNA variants studied remains small, the picture is of age-related penetrance: 29-65% by the age of 50 years and 83-100% by the age of 70 years (FIG.…”

“…26 studied 32 variant carriers aged >40 years, and reported >95% as being affected by DCM. Akinrinade et al 32 , Franaszczyk et al 34 , and Jansweijer et al 79 reported penetrance by decade, yielding a picture of strongly age-related penetrance, but with most variants ultimately penetrant if followed into older age.…”

Thick Filament Protein Network, Functions, and Disease Association

“…Since these domains mediate binding to myosin, it has been speculated that they might lead to defects in contractility, however this has not yet been tested (47). The remaining DCM-associated mutations result from frameshift (37), nonsense (45), and splicing (13) mutations that typically lead to premature stop codons and truncations within the A- and M-band regions of titin (95, 157, 179, 180, 233, 263, 411, 572, 616). Truncated titin molecules missing COOH-terminal epitopes most likely lack sufficient interactions with thick filaments, and therefore, may be unable to appropriately span the sarcomere.…”