An investigation of the clinical profile and extent of Long QT Syndrome (LQTS) associated with the KCNQ1-A341V mutation in South Africa and with the KCNH2-A1116V mutation in an Italian family and the role that autonomic nervous system (ANS) activity and genetics play in clinical variability

[摘要] BackgroundAlthough great progress has been made in defining genes conferring the majority of genetic risk inLong QT Syndrome (LQTS) patients, there remains a substantial challenge to explain the widelyobserved variability in disease expression and phenotype severity, even among family members,sharing the same mutation. Identifying clinical and genetic variables capable ofinfluencing/predicting the clinical phenotype of LQTS patients would allow a more accurate riskstratification, important for determining prognosis, selecting patients for the most appropriatetherapy, and counseling asymptomatic mutation carriers (MCs).To address these questions an Italian LQT2 family and a South African Founder LQT1 populationhave been used.Methods and ResultsItalian LQT2 family. The proband, a 44-yr-old white woman, presented with ventricular fibrillationand cardiac arrest. Intermittent QT prolongation was subsequently observed and LQT2 wasdiagnosed following the identification of a missense KCNH2 mutation (A1116V). The proband alsocarried the common KCNH2 polymorphism K897T on the non-mutant allele. Relatives who carriedA1116V without K897T were asymptomatic but some exhibited transient mild QTc prolongationsuggesting latent disease. Expression studies in Chinese Hamster Ovary (CHO) cells, demonstratedthat the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by theA1116V mutation. These data explain why symptomatic LQTS occurred only in the probandcarrying both alleles.South African LQT1 population. The study population involved 320 subjects, 166 MCs and 154 nonmutation carriers (NMCs). Off ß-blocker therapy, MCs had a wide range of QTc values (406-676ms) and a QTc>500 ms was associated with increased risk for cardiac events (OR=4.22; 95%CI1.12-15.80; p=0.033). We also found that MCs with a heart rate <73 bpm were at significantlylower risk (OR=0.23; 95%CI 0.06-0.86; p=0.035). In a subgroup of patients Baroreflex Sensitivity (BRS) was determined both in presence and absence of ß-blocker therapy. BRS, analyzed insubjects in the 2nd and 3rd age quartiles (age 26-47) to avoid the influence of age, was lower amongasymptomatic than symptomatic MCs (11.8±3.5 vs 20.1±10.9 ms/mmHg, p<0.05). A BRS in thelower tertile carried a lower risk of cardiac events (OR 0.13, 95%CI 0.02-0.96; p<0.05). This studyalso unexpectedly determined that KCNQ1-A341V was associated with greater risk than thatreported for large databases of LQT1 patients: A341V MCs were more symptomatic by age 40(79% vs 30%) and became symptomatic earlier (7±4 vs 13±9 years), both p<0.001. Accordingly,functional studies of KCNQ1-A341V in CHO cells with KCNE1, identified a dominant negativeeffect of the mutation on wild-type channels.ConclusionOur findings indicate that risk stratification for LQTS patients must be more individually tailoredand may have to take into account the specific mutation and probably additional clinical and geneticvariables capable of influencing/predicting the clinical phenotype of LQTS patients. As a matter offact, we have provided evidence that a common KCNH2 polymorphism may modify the clinicalexpression of a latent LQT2 mutation and the availability of an extended kindred with a commonmutation allowed us to highlight that KCNQ1-A341V is associated with an unusually severeclinical phenotype and to identify two autonomic markers, HR and BRS, as novel risk factors.

[发布机构] Stellenbosch University