Mutation location and I  Ks regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region

Abstract

Aims Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. Methods and results Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation. Conclusion KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.

Continuous Bayesian Variant Interpretation Accounts for Incomplete Penetrance among Mendelian Cardiac Channelopathies

“…We observe that the high pathogenicity of variants in the S5 helix continues into the S6 helix of KV7.1 (p.Ala344Val, 17 of 20 heterozygotes affected; p.Gly345Arg, 2 of 2 heterozygotes affected; p.Leu353Pro, 8/8 heterozygotes affected), whereas those for Kv11.1 rapidly taper (residue p.Met645 -4 unique variants -9/10 heterozygotes affected; p.Ser660Leu, 2/7 heterozygotes affected). This finding is consistent with a recent report implicating variants in the Kv7.1 S6 domain as particularly pathogenic, causing a significant decrease in event-free survival 28 . This may be structurally rationalized by the greater sensitivity of flexible motifs within the Kv7.1 S6 helix including the 'GSG' motif 29 (p.Ser349Trp, 2 of 2 heterozygotes affected, and p.Gly350, 3 variants, 9 of 9 heterozygotes affected).…”

“…Incomplete penetrance is observed even among highly deleterious variants. For example, the KCNQ1 variant p.Ala341Val has sharply decreased event-free survival compared to other KCNQ1 missense variants 28 , but still provokes the phenotype incompletely (301 of 375 heterozygotes manifest LQT1). Extended to all variants observed in at least one heterozygote, Figure 4 shows penetrance estimates for relatively few variants exhibit >90% penetrance (quantified in Figure 4E) and a bimodal distribution for LQT1 and LQT2 penetrance, a loosely bimodal distribution for BrS, and a taper for LQT3.…”

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

“…Also, the location of the variant across the protein is important. In fact, location in the pore region of KCNH2 , 118 the transmembrane location, 118 the S6 segment specifically, 119 and dominant‐negative effect for KCNQ1 , are independent risk factors for cardiac events 120 . Furthermore, some specific pathogenic variants are associated with unusually high clinical severity (high penetrance, long QTc, high incidence of SCD), such as the KCNQ1 ‐A341V 121 or the SCN5A ‐G1631D 108 .…”

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases

“…117 Also, the location of the variant across the protein is important. In fact, location in the pore region of KCNH2, 118 the transmembrane location, 118 the S6 segment specifically, 119 and dominant-negative effect for KCNQ1, are independent risk factors for cardiac events. 120 Furthermore, some specific pathogenic variants are associated with unusually high clinical severity (high penetrance, long QTc, high incidence of SCD), such as the KCNQ1-A341V 121 or the SCN5A-G1631D.…”