Wrestling the Giant
New Approaches for Assessing Titin Variant Pathogenicity
This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
In the recent past, the clinical availability of genetic information has increased exponentially and with it the opportunity to use this information to aid in diagnosis and treatment of cardiovascular disease. One of the greatest challenges we face with this wealth of potentially useful diagnostic information is determining the pathogenicity of the myriad genetic variants identified. Dilated cardiomyopathy (DCM) is a particularly salient example of this challenge. Compared with other inherited cardiovascular diseases, such as long QT syndrome, with a diagnostic yield of genetic testing of ≈80%, only 15% to 40% of DCM genetic tests yield a pathogenic variant.1 This reduced diagnostic capability is due in part to our lack of precision in defining phenotypes, as well as the sheer size and number of genes thought to be involved, rendering the examination of a large number of variants in an individual cumbersome.
Articles, see p 419 and 426
In the current issue, 2 groups have addressed an exemplar of these challenges: Titin (TTN).2,3 TTN encodes the largest human protein, consisting of 364 exons that are spliced into transcripts encoding ≈5000 to 34 000 amino acids. Largely because of its size and the ubiquity of rare variation, many individuals harbor variation in the TTN gene (1%–3% differ from the human reference sequence).4,5 However, significant data support the presence of pathogenic variation in TTN, leading to dilated cardiomyopathies, specifically truncating variants in the A-band. Although consistent cosegregation evidence is lacking,6 such variants clearly have lower prevalence in the healthy population,5,7 highlighting the importance of critical evaluation of clinically observed variation in TTN. In this issue, Hastings et al3 and Deo2 each address this challenge with the use of innovative perspective, proposing novel solutions to the problem of …