Relevance of Truncating Titin Mutations in Dilated Cardiomyopathy

January 28, 2016

As a continuation to Blueprint Genetics recent collaborative studies on genetics of dilated cardiomyopathy (DCM) (Eur Heart J 2015 and PlosOne 2015), we performed meta-analysis of truncating titin variants in DCM. Others and we have previously estimated TTN truncating variants (TTNtv) – nonsense, frameshift and consensus splice site, to be responsible for 18-25% of familial cases of DCM and 11-15% of sporadic cases in large patient cohorts (Herman et al. 2012, Roberts et al. 2015, Haas et al. 2015, Akinrinade et al. 2015 and Akinrinade et al. 2016). However, clinical interpretation of these variants is known to be challenging, as these variants are also present rarely in reference populations. Our previous study showed that one in 500 individuals carries a truncation in TTN A-band suggesting that the penetrance of these potentially harmful variants is still not fully understood (Akinrinade et al. 2015). Thus, further research was warranted.

Table. Meta-analysis showed enrichment of TTN truncations in DCM patients (n=1768) vs. reference population (n=60,000)

Titin region DCM vs. reference P-value
A-band 12.25% vs. 0.19% p=1.3×10-251
I-band 2.52% vs. 0.07% p=1.9×10-46
M-band 0.62% vs. 0.05% p=3.2×10-08
Z-disk 0.17% vs. 0.03% p=2.4×10-02

Akinrinade et al. 2016, PubMed: 26777568.


Truncating TTN variants affecting five out of seven transcripts in DCM patient were estimated to be disease causing in at least 97.8% of cases (likelihood ratio 42.2). This is an important step towards a better understanding of the titin truncations in cardiomyopathies.

This calls for caution when interpreting TTNtv in individuals and families with or without history of DCM. Considering the size of TTN, expertise in NGS strategies, bioinformatics, systematic variant assessment strategy, and confirmatory sequencing are prerequisites for reliable evaluation of TTN in clinical settings. Importantly, meaningful interpretation of these variants require understanding of structure of titin protein and its isoforms.

Read more about our collaborative achievements in the article published in Clinical Genetics on January 16th, 2016. Link


(1) Akinrinade O, Alastalo TP, Koskenvuo JW. Relevance of Truncating Titin Mutations in Dilated Cardiomyopathy. Clin Genet. 2016 Jan 18, Epub ahead of print. PubMed 26777568. In collaboration with Blueprint Genetics.

(2) Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenperä P, Koillinen H, Kaartinen M, Nieminen MS, Myllykangas S, Alastalo TP, Koskenvuo JW, Heliö T. Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J. 2015 Sep 7;36(34):2327-37. PubMed 26084686. In collaboration with Blueprint Genetics.

(3) Akinrinade O, Koskenvuo JW, Alastalo TP. Prevalence of Titin Truncating Variants in General Population. PLoS One. 2015 Dec 23;10(12):e0145284. doi: 10.1371/journal.pone.0145284. PubMed 26701604. In collaboration with Blueprint Genetics.

(4) Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. 2015 May 7;36(18):1123-35a. PubMed 25163546.

(5) Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PubMed 22335739.

(6) Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015 Jan 14;7(270):270ra6. PubMed 25589632.

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