Abstract
Despite the overrepresentation of Kv7.1 mutations among patients with a robust diagnosis of long QT syndrome (LQTS), a background rate of innocuous Kv7.1 missense variants observed in healthy controls creates ambiguity in the interpretation of LQTS genetic test results. A recent study showed that the probability of pathogenicity for rare missense mutations depends in part on the topological location of the variant in Kv7.1’s various structure-function domains. Since the Kv7.1’s C-terminus accounts for nearly 50 % of the overall protein and nearly 50 % of the overall background rate of rare variants falls within the C-terminus, further enhancement in mutation calling may provide guidance in distinguishing pathogenic long QT syndrome type 1 (LQT1)-causing mutations from rare non-disease-causing variants in the Kv7.1’s C-terminus. Therefore, we have used conservation analysis and a large case-control study to generate topology-based estimative predictive values to aid in interpretation, identifying three regions of high conservation within the Kv7.1’s C-terminus which have a high probability of LQT1 pathogenicity.
Original language | English (US) |
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Pages (from-to) | 187-197 |
Number of pages | 11 |
Journal | Journal of cardiovascular translational research |
Volume | 8 |
Issue number | 3 |
DOIs | |
State | Published - Apr 1 2015 |
Keywords
- Conservation analysis
- Estimated predictive value
- KCNQ1 (Kv7.1)
- Long QT syndrome
ASJC Scopus subject areas
- Molecular Medicine
- Genetics
- Pharmaceutical Science
- Cardiology and Cardiovascular Medicine
- Genetics(clinical)