Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes

Abstract

BackgroundLong QT syndromes (LQTS) are characterized by prolonged QTc interval on electrocardiogram (ECG) and manifest with syncope, seizures or sudden cardiac death. Long QT 1–3 constitute about 75% of all inherited LQTS. We classified a cohort of Indian patients for the common LQTS based on T wave morphology and triggering factors to prioritize the gene to be tested. We sought to identify the causative mutations and mutation spectrum, perform genotype-phenotype correlation and screen family members.MethodsThirty patients who fulfilled the criteria were enrolled. The most probable candidate gene among KCNQ1, KCNH2 and SCN5A were sequenced.ResultsOf the 30 patients, 22 were classified at LQT1, two as LQT2 and six as LQT3. Mutations in KCNQ1 were identified in 17 (77%) of 22 LQT1 patients, KCNH2 mutation in one of two LQT2 and SCN5A mutations in two of six LQT3 patients. We correlated the presence of the specific ECG morphology in all mutation positive cases. Eight mutations in KCNQ1 and one in SCN5A were novel and predicted to be pathogenic by in-silico analysis. Of all parents with heterozygous mutations, 24 (92%) of 26 were asymptomatic. Ten available siblings of nine probands were screened and three were homozygous and symptomatic, five heterozygous and asymptomatic.ConclusionsThis study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members.

Mutational spectrum of congenital long QT syndrome in Turkey; identification of 12 novel mutations across KCNQ1, KCNH2, SCN5A, KCNJ2, CACNA1C, and CALM1

“…At the protein level, we also found that the variants in KCNQ1 often affected the transmembrane spanning domains similar to previous studies 9,17–19 . So far, there is no clear genotype–phenotype correlation for the variants reported in the KCNQ1 .…”

“…For variants detected in KCNQ1 , the c.1097A>G variant was remarkable since it was observed in 30% of our entire patients. This variant has been reported as isolated case reports associated with LQTS, mainly in Turkish patients 14–18 . Besides, ın a comprehensive study performed on 2500 unrelated LQTS patients, mainly from the USA, only one individual reported with c.1097C>G. Since the KCNQ1 c.1097G>A variant emerged as the major allele in our cohort, this has brought into mind the possibility of being a founder mutation for the Turkish population 14 .…”

Genotype and clinical characteristics of congenital long QT syndrome in Thailand

“…Those with mutation in each of these particular gene have different clinical characteristics and are associated with different triggering events for arrhythmia as well as response to treatment [ 6 ]. There were reports on various gene mutation frequency in Asian countries [ [7] , [8] , [9] , [10] , [11] , [12] ]. From a previous study in Thai children, the ratio of LQTS patients who had cardiac events at rest or sleep appeared to be higher than those found in other Asian countries [ 13 ].…”

Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

“…Note that we used the LQTS-like F351A mutant, because the LQTS mutant F351S did not generate any currents (Figure 1—figure supplement 1). However, during the review process of this manuscript a new LQTS mutation, F351L, was found (Vyas et al, 2016). The current and fluorescence of this LQTS mutant is very similar to the current and fluorescence of F351A (Figure 3—figure supplement 3), suggesting that our conclusions on the LQTS-like F351A is also relevant for the LQTS mutant F351L.…”