title: Enhancing the Predictive Power of Mutations in the C-Terminus of the KCNQ1-Encoded Kv7.1 Voltage-Gated Potassium Channel.
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.
authors: Mayo Medical School, Mayo Clinic, Rochester, MN, USA.
authors: Jamie D
authors: JD
authors: Kapplinger
authors: Andrew S
authors: AS
authors: Tseng
authors: Benjamin A
authors: BA
authors: Salisbury
authors: David J
authors: DJ
authors: Tester
authors: Thomas E
authors: TE
authors: Callis
authors: Marielle
authors: M
authors: Alders
authors: Arthur A M
authors: AA
authors: Wilde
authors: Michael J
authors: MJ
authors: Ackerman
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D003198:Computer Simulation; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010641:Phenotype; D011237:Predictive Value of Tests; D011487:Protein Conformation; D012307:Risk Factors; D029597:Romano-Ward Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013329:Structure-Activity Relationship
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human