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Relevance of truncating titin mutations in dilated cardiomyopathy
Author(s) -
Akinrinade O.,
Alastalo T.P.,
Koskenvuo J.W.
Publication year - 2016
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12741
Subject(s) - titin , dilated cardiomyopathy , population , cardiomyopathy , cardiology , medicine , disease , exome , genetics , exome sequencing , gene , biology , mutation , heart failure , sarcomere , environmental health , myocyte
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.