Response to Letter Regarding Article, “Closer Look at Genetic Testing in Long-QT Syndrome: Will DNA Diagnostics Ever Be Enough?”
Regarding my editorial,1 Dr Kaufman writes that genotype can be “very useful” in those who meet the clinical criteria for the long-QT syndrome in that it may stratify risk and identify the optimum therapy. Although such claims are often made, it is remarkably difficult to demonstrate that a specific genetic variant confers additional information on risk or on the natural history of long-QT syndrome. The studies cited did not control for mode of presentation or confounding familial relationships and modeled risk on the basis of small numbers of events (with unknown interdependence).2,3 Importantly, these studies also did not include simple clinical variables such as personal or family history of events, rest or exercise ECG variables, or drug responses and their conclusions have never been prospectively validated. The relationship between genotype and outcomes is extremely complex, even within a single long-QT syndrome family sharing the same primary causal mutation. It is perhaps not surprising that QTc itself remains the most robust predictor of individual risk because it integrates not only the effects of other genes but also epigenetic and environmental modifiers.2 Even proponents of DNA diagnosis and risk assessment are genotype agnostic when it comes to therapy.4
Dr Kaufman also suggests that genotyping may be useful for borderline phenotypes in which the mutation is “known.” The high de novo mutation rate and the difficulty in defining pathogenicity, even with modern in vitro functional studies, render interpretation of a given sequence variant highly dependent on segregation within the individual kindred.5 Thus, except in the rare instances when there are prior robust data on causality for the specific mutation, the genotype is only as good as the associated clinical information. In large kindreds with high penetrance in whom the causality of a known DNA variant is rigorously defined, truly borderline phenotypes in which genotyping may be useful are unlikely to occur. In contrast, in small kindreds or for individual probands, the pathogenicity of a given variant is often difficult to establish and is only further undermined by attributing causality on the basis of combining uncertain sequence data with indeterminate phenotypes. This type of circular logic has led to the contamination of mutation databases with large numbers of simple polymorphisms.
The range of outcomes within individual long-QT syndrome families demonstrates that binary DNA sequence data at a single locus are unlikely ever to suffice for clinical decision making in conditions in which sudden death is a presenting feature. My comments were not intended to be nihilistic but rather to highlight the need for much more rigorous studies of the relationship between genotype, repolarization biology, and clinically meaningful outcomes. Genetics may identify the underlying disease pathways, but we need to be able to capture more granular data on other inherited components of risk and to characterize the functional status of the relevant pathways in the individual patient if we are to be able to realize the goals of “DNA diagnostics.”
MacRae CA. Closer look at genetic testing in long-QT syndrome: will DNA diagnostics ever be enough? Circulation. 2009; 120: 1745–1748.
Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. 2009; 120: 1761–1767.
Ho CY, MacRae CA. Defining the pathogenicity of DNA sequence variation. Circ Cardiovasc Genet. 2009; 2: 95–97.