Calcium regulation plays a central role in cardiac function. Several variants in the L-type calcium channel, Cav1.2, have been implicated in inherited arrhythmic disorders leading to sudden death. There is a clear need to explore the function of new variants of Cav1.2 channel to gain a better understanding of life-threatening conditions triggered by these variants.

We screened a cohort of patients suffering from Brugada syndrome, short QT syndrome, early repolarization syndrome and idiopathic ventricular fibrillation to identify variants in Cav1.2 coding genes in order to determine their frequency and their functional consequences.

Cav1.2 related genes (CACNA1C, CACNB2 and CACNA2D1) were screened in 65 probands by high resolution melting and Sanger sequencing, or by exome sequencing to identify variants. The conservation, location and frequency of these variants were determined from genetic databases. Missense variants were introduced in Cav1.2 alpha subunit plasmids by directed mutagenesis to perform electrophysiological studies after transfection of TsA-201 cells in order to assess their pathogenicity.

Six missense variants were identified in five individuals. Five of them, p.A1648T, p.A1689T, p.G1795R, p.R1973Q, p.C1992F, did not alter the channel function. The sixth variant, p.T1787M, was identified in two patients with resuscitated cardiac arrest. The first patient originated from Cameroon and presented with an early repolarization syndrome and the second was an inhabitant of La Reunion Island with idiopathic ventricular fibrillation originating from Purkinje tissues. Patch-clamp analysis revealed that this variant significantly reduces the barium current compared to the wild-type channel without affecting the biophysical properties of the Cav1.2 channel.

We identified a loss-of-function variant, Cav1.2-T1787M, a probable risk factor for ventricular fibrillation, only present in the African population.