Résumé :
|
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare familial arrhythmogenic disease, characterized by syncope or sudden death induced by emotional or physical stress. The mortality rate in untreated individuals ranges from 30 to 50% by the age of 40. Since beta blockers and/or implantable cardioverter defibrillator (ICD) can partially prevent arrhythmias and sudden death, early diagnosis through clinical and genetic screening is therefore essential. Mutations in the cardiac isoform of the ryanodine receptor gene (RYR2) have been associated with autosomal dominant forms of CPVT.We report here a familial form of CPVT the case of a 7-yearold boy referred for CPVT after syncope at effort and positive exercise stress test. CPVT was strongly suspected in his mother that showed bidirectional ventricular tachycardia during exercise stress test and in the proband's brother who died suddenly at age 9 after several episodes of syncope during exercise.After written informed consent, RYR2 genetic analysis was performed by direct sequencing in patient's DNA and a heterozygous c.11836G>A; p.Gly3946Ser mutation in exon 88 was identified. This mutation occurred in a highly conserved amino acid position, was not observed among 200 control chromosomes, and has been already been reported twice in association with CPVT.The mutation was absent from the father's and the living sibling's DNA. DNA from the deceased brother was unfortunately not available. Direct sequencing of the mother's DNA did not detect the mutated residue at position c.11836. CPVT was however suspected on clinical basis, which suggested the existence of a mosaicism. The cloning of the PCR amplicons from mother's DNA and the sequencing of the clones allowed us to identify the presence of the mutated sequence from mother's DNA.The somatic maternal mosaicism demonstrated by DNA analysis, and the existence of two children presenting with a CPVT phenotype, were strong evidence for a germline maternal mosaicism.To our knowledge, this is the first case of a somatic mosaicism for a mutation of the RYR2 gene associated with a clinical phenotype. Several cases of mosaicism for a mutation of the RYR2 gene have been published recently but the patient concerned was asymptomatic. This report illustrates that in the case of a germline and somatic mosacism, the patient concerned and its the offspring would be at risk for CPVT depending on the level of mosaicism in heart tissue and in the germline cells respectively.
|