New description of a family with an autosomal recessive cathecholergic ventricular tachycardia due to Triadin gene

Abstract

We describe a family with suspicion of genetic arrhythmia that has benefited from a wide genetic exploration. The eldest of the siblings presented syncope at age 5.5 years and cardiac explorations were normal. A few months later, her elder sister presented a sudden death at age 4.5 years, while she was playing in the garden. The cardiac explorations showed a heart of normal structure but presence of polymorphic premature ventricular complexes. Isoprenaline test was positive. Treatment with beta-blockers (nadolol 50 mg/m 2 ) was introduced. There was no family history of sudden death or other cardiac defects. Because of these two serious rhythmic events occurring in two young children, a genetic study was initiated by next generation sequencing of 42 genes involved in cardiac arrhythmias (long QT, Brugada, cathecholaminergic ventricular tachycardia). Two heterozygous mutations (c.613C > T/p.Gln205* and c.22 + 29 A > G) were identified in the Triadin gene, coding for a protein of the calcium release complex, recently involved in cathecholaminergic ventricular tachycardia in two families (Roux-Buisson et al., 2012). The parents of our two cases were each carriers of a heterozygous mutation and had no cardiac symptoms. Their cardiac assessment did not show any abnormality (ECG Holter, exercise test, Isoprenaline test). The nonsense p.Gln205* mutation was present in one of the published families; however the splicing mutation in intron 1 had never been identified. Minigene experiments helped to confirm its pathogenicity. Presymptomatic testing was then proposed to the third child of the family (age 3), finding the two pathogenic mutations. She was therefore put under the same treatment as her sisters. This is the second report of an autosomal recessive cathecholaminergic ventricular tachycardia due to the Triadin gene. This case illustrates the interest of Next Generation Sequencing exploring simultaneously several candidate genes, in cases of sudden death of unknown origin.