Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients sufferin... 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.
Long QT syndrome (LQTS) is predominantly a genetic cardiac arrhythmia disorder. We report here ou... 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.
Introduction: Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an a... 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.
SCN5A overlap syndromes are clinical entities that express a phenotype combining aspects of diffe... 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.
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the co... 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.
Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients sufferin... 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.
Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients sufferin... 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.
Long QT syndrome (LQTS) is predominantly a genetic cardiac arrhythmia disorder. We report here ou... 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.
Introduction: Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an a... 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.
SCN5A overlap syndromes are clinical entities that express a phenotype combining aspects of diffe... 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.
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the co... 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.
Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients sufferin... 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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Papers by Zahurul Bhuiyan