Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome

Abstract

BackgroundHypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here we report novel trigenic mutations detected in a Chinese family of obstructive HCM with ER and short QT syndrome (SQTS).MethodsProband and family members underwent detailed medical assessments. DNAs were extracted from peripheral blood leukocytes for genetic screening with next generation method. The functional characterization of the mutation was conducted in TSA201 cells with patch-clamp experiment.ResultsThe proband was a 52-year-old male who had a ER pattern ECG in inferioral-lateral leads with atrioventricular block and QTc of 356 ms. He also suffered from severe left ventricular hypertrophy and dysfunction. Targeted sequencing revealed trigenic mutations: c.700G>A/p.E234K in DES, c.2966G>A/p.R989H in MYPN, and c.5918G>C/p.R1973P in CACNA1C. All mutations were also detected in his daughter with ER and mild myocardium hypertrophy. The CACNA1C-R1973P mutation caused significant reduction (68.4%) of ICa compared to CACNA1C-WT (n = 14 and 14, P < 0.05). The computer modeling showed that all 3 mutations were highly disease-causing. The proband received the CRT-D (cardiac resynchronizing therapy) implantation, which lowered the left ventricular outflow tract gradient (LVOTG, 124 mmHg pre vs. 27 mmHg post) and restored the LV function (LVEF 40% pre vs. 63% post).ConclusionsThe study reveals a novel CACNA1C mutation underlying the unique ER pattern ECGs with SQTS. It also shows the rare trigenic mutations are the pathogenic substrates for the complicated clinical manifestation in HCM patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1180-1) contains supplementary material, which is available to authorized users.

Learning from studying very rare cardiac conditions: the example of short QT syndrome

“…For nearly all of the ion channel gene mutations implicated in the SQTS, detailed cellular electrophysiology study using patch clamp electrophysiology has been performed. Such recordings have demonstrated the gain-of-function consequences of SQT1-SQT3 K + mutations [15,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] and loss-of-function consequences of Na and Ca channel subunit mutations [36,[56][57][58][59]. With an historical lack of genotypically accurate mammalian models of the SQTS, computational modelling has been employed to determine the consequences of altered channel function for repolarization.…”

“…Thus, the degree to which KCNJ2 gain-of-function mutations alter AP repolarization can be linked to the severity of the underlying mutant's effects on Kir2.1 channel function and the range of voltages over which outward Kir2.1 current is augmented. SQT4-6 variants involve loss of function mutations to genes encoding L-type Ca channel subunits (CACNA1C, CACNB2b, CACNA2D1) [36,56,57,59]. In each case, the observed mutations lead to reductions in L-type Ca current in vitro.…”

“…In each case, the observed mutations lead to reductions in L-type Ca current in vitro. Patients exhibit a mixed Brugada/SQTS phenotype, combining changes in ST segment morphology (with or without drug testing) with QT c abbreviation [36,56,57,59]. For example, in the first study associating CACNA1C with Brugada/SQTS, the 44 year-old male patient with the A93V mutation presented with marked ST segment elevation in ECG lead V 1 , saddle-back elevation in lead 2 and a prominent J wave in lead 3.…”

Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias

“…It is an autosomal-dominant disease with five identified causative genes, including three that encode for K + channels (KCNH2, KCNQ1, and KCNJ2) and two that encode for subunits of the L-type Ca 2+ channels (CACNA1C and CACNB2). [49][50][51] Mutations in the Ca V 1.2 genes CACNA1C and CACNB2b have also been associated with both idiopathic ventricular fibrillation and early repolarization syndrome. 43 A mutation in CACNA1D, which encodes Ca V 1.3, was identified in a Pakistani family with pronounced bradycardia resulting from nonconducting Ca V 1.3 channels.…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…However, the roles of p.R1977Q mutation in SQTS are still unknown. Recently, a novel CACNA1C mutation p.R1937P was reported in a Chinese family of hypertrophic cardiomyopathy with early repolarization and SQTS, p.R1937P induced the loss-of-function of Ca V 1.2 channels, which dramatically decreased the I Ca and hyperpolarized the SSI [116]. …”