Clin Genet. 2016 Jan 18. doi: 10.1111/cge.12741.

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.

Abstract

Dilated cardiomyopathy (DCM), a genetically heterogeneous cardiac disease characterized by left ventricular dilatation and systolic dysfunction, is caused majorly by truncations of titin (TTN), especially in A-band region. Clinical interpretation of TTN-truncating variants (TTNtv) has been challenged by the existing inaccurate variant assessment strategies and uncertainty in the true frequency of TTNtv across the general population. We aggregated TTNtv identified in 1788 DCM patients and compared the variants with those reported in over 60,000 Exome Aggregation Consortium reference population. We implemented our current variant assessment strategy that prioritizes TTNtv affecting all transcripts of the gene, and observed a decline in the prevalence of TTNtv in DCM. Despite this decline, TTNtv are more prevalent in DCM patients compared with reference population (p = 4.1 × 10(-295) ). Moreover, our extended analyses confirmed the enrichment of TTNtv not only in the A-band but also in the I/A-band junction of TTN. We estimated the probability of pathogenicity of TTNtv affecting all transcripts of TTN, identified in unselected DCM patients to be 97.8% (likelihood ratio (LR) = 42.2). We emphasize that identifying a TTNtv, especially in the A-band region, has a higher risk of being disease-causing than previously anticipated, and recommend prioritizing TTNtv affecting at least five transcripts of the gene.

Akinrinade O, Koskenvuo JW, Alastalo TP