Truncations of Titin Causing Dilated Cardiomyopathy

Abstract

BACKGROUND Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. METHODS We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hyper-trophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics. RESULTS We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P = 3×10−16) or controls (7 of 249 [3%], P = 9×10−14). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P = 4×10−5). CONCLUSIONS TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.)

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

“…The TTN A-band was enriched for truncating variants in DCM probands as compared with controls (odds ratio = 14.6; 99% confidence interval: 4.32-58.5; P < 2 × 10 −10 ). The frequency in controls as well as the clustering of variants in the A-band in probands is consistent with results reported by Herman et al 23 In addition, our data showed a reduced frequency of variants in the I-band in probands as compared with controls (odds ratio = 0.13; 99% confidence interval: 0.04-0.43; P < 2 × 10 −6 ). No difference in frequency was detected in the Z-and M-bands (Figure 3).…”

“…From an analysis of 312 DCM patients and 249 controls, Herman et al 23 reported a clustering of truncating variants in the A-band 23 To validate and expand on this finding, we combined the variants from Herman et al 23 (n = 55) with TTN -truncating variants detected in our study (n = 18). The NHLBI ESP cohorts (~6,500 individuals of European or African-American ancestry) served as a control cohort, representing the general population.…”

“…23 We identified 152 missense TTN VUSs that drove a surge of the above-mentioned inconclusive test results ( Figure 1). The second highest contributor was LMNA (4.1-4.5%), followed by MYH7 (3.4-4.9%).…”

“…We compared titin (TTN) variants from our cohort and from cases published by Herman et al 23 ("probands") with those detected in ~6,500 individuals sequenced by ESP (downloaded 21 January 2013, "controls"). The observed distribution of variants across the gene was compared with the expected frequencies for the same gene using a binomial test with expected frequencies determined by the fraction of the overall sequence represented by each band.…”

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

“…Prominent examples include MYBPC3 , which explains 15–20% of hypertrophic cardiomyopathy (HCM) and TTN , which is responsible for 10–25% of dilated cardiomyopathy (DCM) (Herman et al. 2012; Teekakirikul et al. 2013; Pugh et al.…”