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Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients suffering from channelopathies or hereditary cardiomyopathies. Mutation is discovered in around 50 % of the cases. Several experts are working... more
Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients suffering from channelopathies or hereditary cardiomyopathies. Mutation is discovered in around 50 % of the cases. Several experts are working together to bring probands and their families useful and necessary informations to help them understanding causes, consequences and support of their disease. This approach is developped in close collaboration with the treating physician.
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Long QT syndrome (LQTS) is predominantly a genetic cardiac arrhythmia disorder. We report here our study on long QT syndrome from two children from Kelantan, Malaysia. Clinical and genetic findings of these two unrelated Malay children... more
Long QT syndrome (LQTS) is predominantly a genetic cardiac arrhythmia disorder. We report here our study on long QT syndrome from two children from Kelantan, Malaysia. Clinical and genetic findings of these two unrelated Malay children with LQTS is discussed. We found a Long QT, type 1 causal mutation, p.Ile567Thr in the KCNQ1 gene in the first child. A pathogenic mutation could not be detected in the second child, explaining the heterogeneity of this disease.
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Introduction: Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an autosomal dominantly inherited disease with incomplete penetrance and highly variable expression. Mutations in genes encoding 5 desmosomal... more
Introduction: Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an autosomal dominantly inherited disease with incomplete penetrance and highly variable expression. Mutations in genes encoding 5 desmosomal proteins and TMEM43 usually underlie ARVD/C. Aim: Comprehensive sequencing of all 6 genes in a large cohort of Dutch ARVD/C patients (pts) correlated with phenotypic characteristics. Methods: Inclusion of 109 ARVD/C pts (81 men, age 49±14 yrs) according to diagnostic Task Force Criteria (TFC). Clinical history and data on separate TFC were collected. DNA of all 109 pts was directly sequenced for mutations in desmosomal genes PKP2, DSC2, DSG2, DSP and JUP. In 81 cases TMEM43 was also analyzed. Pathogenic mutations were defined as DNA sequence variations disrupting conserved residues and not present in 200 ethnically-matched controls. Clinical characteristics were related to specific genes, type (truncating or not) and number of mutations. Results: In 63 of 109 pts (58%) single mutations were observed: 19 different PKP2 mutations in 57 cases, 5 in DSG2 and 1 in DSC2. Five more pts carried 2 mutations: in PKP2 and additionally in DSG2 (n=2), DSP (n=2) or TMEM43 (n=1). Mutations occurred equally in men and women. Phenotype variations were not related to gene or type of mutations. First arrhythmic event was at significantly younger age in pts with mutation than those without, and youngest in those 5 pts with bigenic involvement (mean age for 0, 1 and 2 mutations: 43, 34 and 21 yrs, resp). Also, between groups with 0, 1 and 2 mutations, occurrence of negative T waves in leads V1-3 (41, 80 and 100%, resp) and major structural abnormalities (46, 65 and 100% resp) was significantly different. Frequency of all other parameters was similar. Conclusions: In 68 of 109 (62%) Dutch ARVD/C patients pathogenic mutations were observed, mainly in PKP2, with multiple mutations in 5 cases. Mutation carriers more often had negative T waves in V1-3 and structural abnormalities. Moreover, they presented at younger age than patients without mutations; this age was even younger when multiple genes were affected. Screening of all relevant genes is needed for appropriate genotype-phenotype correlation.
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SCN5A overlap syndromes are clinical entities that express a phenotype combining aspects of different canonical SCN5A-related arrhythmia syndromes or a variable arrhythmic phenotype among individuals carrying the same SCN5A mutation. We... more
SCN5A overlap syndromes are clinical entities that express a phenotype combining aspects of different canonical SCN5A-related arrhythmia syndromes or a variable arrhythmic phenotype among individuals carrying the same SCN5A mutation. We here review the literature addressing SCN5A overlap syndromes, as well as the principal mechanisms currently proposed. Among others, a multifactorial determination - encompassing an interaction between SCN5A variant(s), other genetic polymorphisms, and possibly environmental factors - seems the most plausible hypothesis.
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Research Interests: Cardiology, Medicine, Electrocardiography, DNA, Cell line, and 15 moreHumans, Internal Medicine, Mutation, Female, Male, Infant, Long QT syndrome, Pedigree, Clinical Sciences, Family Health, Public health systems and services research, Circulation, QT interval, Age of Onset, and Cardiovascular medicine and haematology
Research Interests: Biomedical Engineering, Medicine, Electrocardiography, Humans, Internal Medicine, and 12 moreMutation, Male, Infant, Switzerland, Long QT syndrome, Calmodulin, Action Potentials, QT interval, Bradycardia, Child preschool, Cardiovascular medicine and haematology, and Genetic predisposition to disease
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Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the congenital long QT syndrome (LQTS). We identified two novel CaM mutations in children with LQTS associated with cardiac arrest, and performed... more
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the congenital long QT syndrome (LQTS). We identified two novel CaM mutations in children with LQTS associated with cardiac arrest, and performed studies to elucidate the functional consequences of each molecular defect. The first mutation was discovered in a male infant with a ventricular septal defect and fetal bradycardia born to healthy parents. His ECG on postnatal day 1 revealed bradycardia and very prolonged QTc (651 msec). At age 2-days, he developed 2:1 AV block, profound bradycardia (50 bpm) and cardiogenic shock. He was resuscitated and received a pacemaker. Targeted DNA sequencing revealed a de novo mutation in CALM2 (D132H). A second novel mutation was discovered in a three year-old boy who suffered witnessed cardiac arrest. His initial rhythm was ventricular fibrillation, and after successful defibrillation an ECG recording revealed a QTc of 574 msec. The parents were healthy with normal QTc intervals. Exome sequencing of the parent-child trio demonstrated a de novo mutation in CALM1 (D132V). Both novel mutations affect the same conserved aspartate residue within the C-domain EF-hand-IV Ca2+ binding motif. Further studies elucidated biochemical and functional effects of the mutations. Measurements of Ca2+ binding affinity of CaM-D132H indicated extremely weak binding to the C-domain (Kd > 150 μM) with significant structural perturbations. Voltage-clamp recordings of human induced pluripotent stem cell (iPSC) derived cardiomyocytes transiently expressing wildtype or mutant CaM demonstrated that both mutations caused impaired Ca2+-dependent inactivation (CDI) of voltage-gated Ca2+ current. Neither mutant affected voltage-dependent inactivation of Ba2+ currents. Our findings implicate impaired CDI in human cardiomyocytes as the plausible mechanism for LQTS associated with CaM mutations.
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Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients suffering from channelopathies or hereditary cardiomyopathies. Mutation is discovered in around 50 % of the cases. Several experts are working... more
Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients suffering from channelopathies or hereditary cardiomyopathies. Mutation is discovered in around 50 % of the cases. Several experts are working together to bring probands and their families useful and necessary informations to help them understanding causes, consequences and support of their disease. This approach is developped in close collaboration with the treating physician.
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Research Interests: Molecular Biology, Biology, Virology, Medicine, Biological Sciences, and 14 moreVirus, Animals, Genome, Protein Sequence Analysis, Amino Acid Sequence, Base Sequence, Open Reading Frame, Lymphocytes, Right Handed, cDNA library, Molecular Sequence Data, cDNA cloning, Restriction Mapping, and Medical and Health Sciences
Research Interests: Cardiology, Adolescent, Medicine, England, Electrocardiography, and 15 moreHumans, Internal Medicine, Female, Male, Heart, Follow-up studies, Clinical Sciences, Implantable defibrillators-cardioverters, New England Journalof Medicine, Catecholamines, Ventricular Tachycardia, Catecholaminergic polymorphic ventricular tachycardia, Tachycardia, sympathectomy, and Medical and Health Sciences
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Research Interests: Genetics, Cardiology, Biomedical Engineering, Adolescent, Medicine, and 15 moreElectrocardiography, Humans, Internal Medicine, Genetic Testing, Mutation, Female, Middle Aged, Adult, Arrhythmia, Base Sequence, Molecular Sequence Data, frameshift mutation, Heart arrest, Cardiovascular medicine and haematology, and Genetic predisposition to disease
Inherited cardiomyopathies and arrhythmias (ICAs) are a prevalent and clinically heterogeneous group of genetic disorders that are associated with increased risk of sudden cardiac death and heart failure. Making a genetic diagnosis can... more
Inherited cardiomyopathies and arrhythmias (ICAs) are a prevalent and clinically heterogeneous group of genetic disorders that are associated with increased risk of sudden cardiac death and heart failure. Making a genetic diagnosis can inform the management of patients and their at-risk relatives and, as such, molecular genetic testing is now considered an integral component of the clinical care pathway. However, ICAs are characterised by high genetic and allelic heterogeneity, incomplete / age-related penetrance, and variable expressivity. Therefore, despite our improved understanding of the genetic basis of these conditions, and significant technological advances over the past two decades, identifying and recognising the causative genotype remains challenging. As clinical genetic testing for ICAs becomes more widely available, it is increasingly important for clinical laboratories to consolidate existing knowledge and experience to inform and improve future practice. These recomme...
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The gene SCN5A encodes the cardiac sodium channel which, through the conduction of Na+ current into the cell, generates the fast upstroke of the action potential of cardiomyocytes. Pathogenic variants of SCN5A have been causally... more
The gene SCN5A encodes the cardiac sodium channel which, through the conduction of Na+ current into the cell, generates the fast upstroke of the action potential of cardiomyocytes. Pathogenic variants of SCN5A have been causally associated to several hereditary cardiac diseases including, among others, Brugada syndrome, congenital long QT syndrome and sinus node dysfunction. Recently, overlap syndromes have been described that are characterized by the simultaneous expression of mixed clinical phenotypes among two or more hereditary cardiac diseases associated to the gene SCN5A (HCD-SCN5A). For this reason, it is time to rethink about HCD-SCN5A as different expressions of the same complex spectrum encompassing multiple clinical phenotypes with pronounced overlaps instead of as distinct clinical entities.
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IntroductionAlström syndrome, ALMS (OMIM 203800) is a rare multi-systemic disease. The characteristic clinical features include blindness due to progressive cone-rod dystrophy, sensorineural hearing loss, type 2 diabetes mellitus, dilated... more
IntroductionAlström syndrome, ALMS (OMIM 203800) is a rare multi-systemic disease. The characteristic clinical features include blindness due to progressive cone-rod dystrophy, sensorineural hearing loss, type 2 diabetes mellitus, dilated cardiomyopathy, and childhood obesity. The aim of this study was to identify the genetic cause of Alström syndrome in patients who presented with variable clinical characteristics.Material and methodsClinical phenotyping and whole exome sequencing were performed in Saudi Alström syndrome patients. The Sanger sequencing was done to ascertain the segregation of Alström syndrome causative mutation in the family members. The rare prevalence of this mutation was further established by sequencing an additional 100 healthy Saudi controls.ResultsWhole exome sequencing analysis revealed that Alström syndrome patients have inherited a novel homozygous protein truncating mutation (c.2938dupA) in the ALMS1 gene segregated in an autosomal recessive fashion. Thi...
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Background: CaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with... more
Background: CaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with 2 novel calmodulin mutations and to investigate mosaicism in 2 affected families. Methods: CaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation. Results: Genetic studies identified 2 novel CaM variants ( CALM3 -E141K in 2 cases; CALM1 -E141V) and one previously reported CaM pathogenic variant ( CALM3 -D130G) among 4 probands with shared clinical features of prolonged QTc interval (range 505–725 ms) and documented ventricular arrhythmia. A fatal outcome occurred for 2 of the cases. The parents of all probands were asymptomatic with normal QTc duration. However, 2 of the families had multiple affected offspring or multi...
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Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the... more
Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%)...
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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the major causes of sudden death. Myocardial atrophy with subsequent fibro‐fatty replacement predominantly affects right ventricular myocardium and results in global and... more
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the major causes of sudden death. Myocardial atrophy with subsequent fibro‐fatty replacement predominantly affects right ventricular myocardium and results in global and regional dysfunction as well as areas of slow conduction and dispersion of refractoriness, which are prerequisites for reentrant ventricular tachyarrhythmias. ARVC is commonly presented in patients <65 years old. However, few cases of elderly people suffering from this cardiomyopathy have been reported in the literature. We present a case of an 82‐year‐old woman with sustained ventricular tachycardia due to first diagnosed ARVC.
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We sought to explore the genotype-phenotype of Jervell and Lange-Nielsen syndrome (JLNS) patients in Saudi Arabia. We have also assessed the plausible effect of consanguinity into the pathology of JLNS. Six families with at least one... more
We sought to explore the genotype-phenotype of Jervell and Lange-Nielsen syndrome (JLNS) patients in Saudi Arabia. We have also assessed the plausible effect of consanguinity into the pathology of JLNS. Six families with at least one JLNS-affected member attended our clinic between 2011 and 2013. Retrospective and prospective clinical data were collected and genetic investigation was performed. Pathogenic mutations in the KCNQ1 gene were detected in all JLNS patients. The homozygous mutations detected were Leu273Phe, Asp202Asn, Ile567Thr, and c.1486_1487delCT and compound heterozygous mutations were c.820_ 830del and c.1251+1G&amp;amp;amp;amp;gt;T. All living JLNS patients except one had a QTc of &amp;amp;amp;amp;gt;500 ms and a history of recurrent syncope. β-Blockers abolished the cardiac-related events in all patients except two siblings with homozygous Ile567Thr mutation. Four of the six mutations were originally reported in autosomal dominant long QT syndrome (LQTS) patients. Eighty percent of the heterozygote mutation carriers showed prolongation of QTc, but majority of these reported no symptoms attributable to arrhythmias. Mutations detected in this study will be advantageous in tribe and region-specific cascade screening of LQTS in Saudi Arabia.
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Aims Sudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL. However, phenotypes have only begun to be described and no data are available on medical therapy after long-term follow-up.... more
Aims Sudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL. However, phenotypes have only begun to be described and no data are available on medical therapy after long-term follow-up. Methods and results An international, multi-centre retrospective review was conducted. We report new cases associated with TECRL variants and long-term follow-up from previously published cases. We present 10 cases and 37 asymptomatic heterozygous carriers. Median age at onset of cardiac symptoms was 8 years (range 1–22 years) and cases were followed for an average of 10.3 years (standard deviation 8.3), right censored by death in three cases. All patients on metoprolol, bisoprolol, or atenolol were transitioned to nadolol or propranolol due to failure of therapy. Phenotypes typical of both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) were observed. We also observed divergent phenotypes in some cases despite identica...
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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disorder of unknown cause that is characterised by fibrofatty replacement, primarily of the right ventricular myocardium, which can lead to life-threatening... more
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disorder of unknown cause that is characterised by fibrofatty replacement, primarily of the right ventricular myocardium, which can lead to life-threatening arrhythmias. It is a disease with a very diverse phenotype. In the present article we describe two sisters, each with a different manifestation of this disorder. The first patient died
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Background—This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 (PKP2), Desmoglein-2 (DSG2), and Desmocollin-2 (DSC2), in arrhythmogenic right ventricular dysplasia/cardiomyopathy... more
Background—This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 (PKP2), Desmoglein-2 (DSG2), and Desmocollin-2 (DSC2), in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We also aimed to distinguish relevant clinical and ECG parameters. Methods and Results—Clinical evaluation was performed according to the Task Force Criteria (TFC). We analyzed the genes in (a) 57 patients who fulfilled the ARVD/C TFC (TFC), (b) 28 patients with probable ARVD/C (1 major and 1 minor, or 3 minor criteria), and (c) 31 patients with 2 minor or 1 major criteria. In the TFC ARVD/C group, 23 patients (40%) had PKP2 mutations, 4 (7%) had DSG2 mutations, and 1 patient (2%) carried a mutation in DSC2, whereas 1 patient (2%) had a mutation in both DSG2 and DSC2. Among the DSG2 and DSC2 mutation-positive TFC ARVD/C probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. In probable ARVD/C patients and...
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Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and... more
Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in MYH7 (c.2770G > A; p.Glu924Lys). The LAMA4 p.Asp1309As...
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Introduction: Sudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL . Phenotypes have only begun to be described and no data are available on medical therapy after long-term follow-up.... more
Introduction: Sudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL . Phenotypes have only begun to be described and no data are available on medical therapy after long-term follow-up. Methods: An international, multicenter retrospective review was conducted. We report new cases associated with TECRL variants and long-term follow-up from previously published cases. Results: We present 10 cases and 37 asymptomatic heterozygous carriers. Median age at onset of cardiac symptoms was 8 years (range 1-22 years) and cases were followed for an average of 10.3 years (SD 8.3), right censored by death in 3 cases. All patients on metoprolol, bisoprolol or atenolol were transitioned to nadolol or propranolol due to failure of therapy. Phenotypes typical of both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia were observed. We also observed divergent phenotypes in some cases despite identical homozygous variants. None of 3...
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not availableBangladesh Heart Journal 2017; 32(1) : 1-2
Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of... more
Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL Analysis of intracellular calcium ([Ca(2+)]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLHom-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLHet-hiPS...
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ABSTRACT Background: Mutations in PLN are an infrequent cause for FDCM. Yet details on the phenotype are imperfectly defined. Systematic clinical analyses in FDCM patients with PLN mutations were not performed so far Methods: We... more
ABSTRACT Background: Mutations in PLN are an infrequent cause for FDCM. Yet details on the phenotype are imperfectly defined. Systematic clinical analyses in FDCM patients with PLN mutations were not performed so far Methods: We prospectively characterized twenty relatives of a family with FDCM by ECG, Holter-ECG, echocardiography, cardiac magnetic resonance imaging (CMR) and body surface potential mapping (BSPM). Medical records of four deceased relatives were reviewed. The coding region of PLN was directly sequenced. Results: We identified a previously characterized deletion of arginine at codon 14 in PLN (R14Del). Mutation carriers suffered from early onset FDCM associated with severe ventricular arrhythmias and cardiac deaths between ages of 26-50. Disease penetrance was age and gender-dependent. All adult mutation carriers revealed strikingly attenuated R amplitudes in standard ECG. Interestingly, this feature was also present in subjects with normal ejection fraction. Gadolinium enhanced CMR showed significant delayed enhancement in two mutation carriers indicating left ventricular fibrosis as a primary event. By use of BSPM we were able to map the most prominent reduction of R amplitudes to lateral regions of the left ventricle, which was consistent with fibrosis at the corresponding site. Conclusions: We present an early electrocardiographic phenotype in a FDCM family carrying the PLN-R14Del mutation. All adult mutation carriers displayed significantly attenuated R amplitudes regionally linked to primary cardiac fibrosis. Thus, cardiac fibrosis may constitute the anatomic substrate for low electrocardiographic voltages. The results indicate a mutation specific remodelling process preceding ventricular dysfunction. Patients with DCM and low voltage ECG should undergo genetic screening in PLN.