[Show abstract][Hide abstract] ABSTRACT: The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 × ), NKX2-5 (6 × ), ZIC3 (3 × ), MLPA (2 × ) and ELN (4 × ). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.European Journal of Human Genetics advance online publication, 27 May 2015; doi:10.1038/ejhg.2015.105.
European journal of human genetics: EJHG 05/2015; DOI:10.1038/ejhg.2015.105 · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sudden death in childhood is rare, representing only 10 % of paediatric mortality after the age of 1 year. The individual risk is estimated between 1 in 20 000 and 1 in 50 000 per year. In case of a negative autopsy for cardiac morphological anomalies, the most likely cause is a genetically determined malignant primary ventricular arrhythmia. Rhythmic sudden cardiac death can be categorized as a complication of a cardiomyopathy (dilated or hypertrophic) or as a primary channelopathy without any structural heart disease. Primary ventricular arrhythmias include long QT syndrome, Brugada syndrome, short QT syndrome and polymorphic ventricular tachycardia. The diagnosis of such syndromes relies upon specific electrocardiogram anomalies, personal history of family members, eventual echocardiography and drug challenge. Morbid genes have been identified for some of these diseases, thus rendering possible the management of presymptomatic or undiagnosed family members within specialized multidisciplinary teams. In cases of sudden arrhythmic death in children, the parents and siblings must be examined. Rescued sudden death exposes the patient to a high risk of recurrence. In such patients, the automatic implantable defibrillator has dramatically improved survival.
Archives of Cardiovascular Diseases Supplements 09/2012; 4(2):179–192. DOI:10.1016/S1878-6480(12)70829-7
[Show abstract][Hide abstract] ABSTRACT: Regular narrow QRS tachycardia - so-called supraventricular tachycardia - is the most common arrhythmia in the paediatric population. Different mechanisms can be involved: macrore entrant circuit within the atrium (intra-atrial reentrant tachycardiaatrial flutter); re entrant circuit between the atrium and the ventricle (atrioventricular reentrant tachycardia or atrioventricular node reentrant tachycardia); and abnormal automaticity of the atrium (atrial ectopic tachycardia) or the His bundle (junctional ectopic tachycardia). Among infants, the major clinical presentation is failure to thrive. However, a rare patient may present with potentially life-threatening congestive heart failure in case of tachycardia-mediated cardiomyopathy. The natural history of supraventricular tachycardia in children differs according to mechanism and age at presentation. Spontaneous resolution of supraventricular tachycardia beyond age 1–2 years is not rare. In this population, chronic antiarrhythmic medication is the firstline treatment to prevent recurrence. This treatment is maintained until resolution or remission of the arrhythmia. For older children, several different treatment options can be considered, depending on diagnosis, haemodynamic tolerance of the tachycardia and efficacy of the medical treatment. When antiarrhythmic therapy is ineffective or not desired, an ablation procedure offers the possibility of a definitive cure.
Archives of Cardiovascular Diseases Supplements 09/2012; 4(2):148–162. DOI:10.1016/S1878-6480(12)70826-1
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease.
Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias.
Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified.
Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine.
A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine.
Journal of the American College of Cardiology 07/2012; 60(2):144-56. DOI:10.1016/j.jacc.2012.02.052 · 15.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic disorder with a highly malignant clinical course. Exercise-stress test is the first-line approach to diagnose suspected individuals. We sought to elucidate the value of exercise-stress test for predicting mutations and future cardiac events in CPVT-family relatives.
The present study included 67 asymptomatic relatives (24 ± 15 years) of 17 genetically positive CPVT probands, who underwent exercise-stress test without any medication and genetic testing. Exercise-stress test, which was considered positive with the induction of ventricular tachycardia or premature ventricular contractions consisting of bigeminy or couplets, was positive in 17 relatives (25%). Genetic analysis disclosed mutations in 16 of these 17 relatives (94%) and in 16 of the 50 relatives (32%) with negative exercise-stress test; the sensitivity and specificity for a positive genotype were 50 and 97%, respectively (P< 0.001). Among 32 mutation carriers, cardiac events occurred in 7 of the 16 relatives with positive and 2 of the 16 relatives with negative exercise-stress test during the follow-up period of 9.6 ± 3.8 years, and four with positive and two with negative stress test were not on regular beta-blocker treatment at these events. In the 16 relatives with positive stress test, those on beta-blocker treatment demonstrated a trend of lower cardiac event rate (Log-rank P= 0.054).
In asymptomatic relatives of CPVT probands, exercise-stress test can be used as a simple diagnostic tool. Nevertheless, because of the low sensitivity for predicting mutations and future cardiac events in those with negative stress test, genetic analysis should be performed to improve patient management.
[Show abstract][Hide abstract] ABSTRACT: The pathophysiological background of catecholaminergic polymorphic ventricular tachycardia is well understood, but the clinical features of this stress-induced arrhythmic disorder, especially the incidence and risk factors of arrhythmic events, have not been fully ascertained.
The outcome in 101 catecholaminergic polymorphic ventricular tachycardia patients, including 50 probands, was analyzed. During a mean follow-up of 7.9 years, cardiac events defined as syncope, aborted cardiac arrest, including appropriate discharges from implantable defibrillators, or sudden cardiac death occurred in 27 patients, including 2 mutation carriers with normal exercise tests. The estimated 8-year event rate was 32% in the total population and 27% and 58% in the patients with and without beta-blockers, respectively. Absence of beta-blockers (hazard ratio [HR], 5.48; 95% CI, 1.80 to 16.68) and younger age at diagnosis (HR, 0.54 per decade; 95% CI, 0.33 to 0.89) were independent predictors. Fatal or near-fatal events defined as aborted cardiac arrest or sudden cardiac death occurred in 13 patients, resulting in an estimated 8-year event rate of 13%. Absence of beta-blockers (HR, 5.54; 95% CI, 1.17 to 26.15) and history of aborted cardiac arrest (HR, 13.01; 95% CI, 2.48 to 68.21) were independent predictors. No difference was observed in cardiac and fatal or near-fatal event rates between probands and family members.
Cardiac and fatal or near-fatal events were not rare in both catecholaminergic polymorphic ventricular tachycardia probands and affected family members during the long-term follow-up, even while taking beta-blockers, which was associated with a lower event rate. Further studies evaluating concomitant therapies are necessary to improve outcome in these patients.