A5065823316- Congenital heart defects research
- Congenital Heart Disease Studies
- Cardiomyopathy and Myosin Studies
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Coronary Artery Anomalies
- Cardiovascular Effects of Exercise
- RNA modifications and cancer
- Tracheal and airway disorders
- Cardiac Arrhythmias and Treatments
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Genomic variations and chromosomal abnormalities
- Cardiovascular Function and Risk Factors
- Genomics and Rare Diseases
- Neurogenetic and Muscular Disorders Research
- Cardiac Valve Diseases and Treatments
- Cardiac Structural Anomalies and Repair
- Cardiac pacing and defibrillation studies
- Genetics and Neurodevelopmental Disorders
- Connective tissue disorders research
- Physiological and biochemical adaptations
- Renal Diseases and Glomerulopathies
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Cancer-related gene regulation
Amsterdam University Medical Centers
2018-2024
University of Amsterdam
2011-2024
American College of Medical Genetics
2023
Baylor College of Medicine
2023
Vrije Universiteit Amsterdam
2022
Pediatrics and Genetics
2021
Amsterdam UMC Location University of Amsterdam
2010-2019
Amsterdam Neuroscience
2000-2019
University of Manchester
2019
Manchester Metropolitan University
2019
Mutations in SCN5A, the gene encoding cardiac Na(+) channel, have been identified 2 distinct diseases associated with sudden death: one form of long-QT syndrome (LQT(3)) and Brugada syndrome. We screened SCN5A a large 8-generation kindred characterized by high incidence nocturnal death, QT-interval prolongation "Brugada ECG" occurring same subjects. An insertion 3 nucleotides (TGA) at position 5537, predicted to cause an aspartic acid (1795insD) C-terminal domain protein, was linked...
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by syncopal events and sudden cardiac death at young age during physical stress or emotion, in the absence of structural heart disease. We report first nonsense mutations calsequestrin gene, CASQ2, three CPVT families. The mutations, R33X, splicing 532+1 G>A, 1-bp deletion, 62delA, are thought to induce premature stop codons. Two patients who experienced syncopes before 7 years were...
Familial recurrence studies provide strong evidence for a genetic component to the predisposition sporadic, nonsyndromic Tetralogy of Fallot (TOF), most common cyanotic congenital heart disease phenotype. Rare variants have been identified as important contributors risk disease, but relatively small numbers TOF cases studied date.We used whole exome sequencing assess prevalence unique, deleterious in largest cohort patients reported date.Eight hundred twenty-nine underwent sequencing. The...
Background— Catecholaminergic polymorphic ventricular tachycardia is a disease characterized by arrhythmias elicited exclusively under adrenergic stress. Additional features include baseline bradycardia and, in some patients, right fatty displacement. The clinical spectrum expanded the 2 families described here. Methods and Results— Sixteen members from separate have been clinically evaluated followed over last 15 years. In addition to exercise-related arrhythmias, they showed abnormalities...
Holt-Oram syndrome (HOS) is a heart/hand clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome. Here, we describe large atypical HOS family which affected patients have mild skeletal deformations paroxysmal atrial fibrillation, but few congenital heart disease. Sequencing of TBX5 revealed novel mutation, c.373G>A, resulting the missense mutation p.Gly125Arg, all investigated members, cosegregating with We...
Background— Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets tricuspid valve to underlying myocardium. An association between with left ventricular noncompaction (LVNC) mutations in MYH7 encoding β-myosin heavy chain has been shown; this report, we have screened for cohort probands large population-based study. Methods Results— Mutational analysis 141 unrelated was performed next-generation sequencing direct DNA ....
The endothermic state of mammals and birds requires high heart rates to accommodate the oxygen consumption. These are driven by very similar conduction systems consisting an atrioventricular node that slows electrical impulse a His-Purkinje system efficiently activates ventricular chambers. While ectothermic vertebrates have contraction patterns, they do not possess anatomical evidence for system. This lack amongst extant ectotherms is surprising because evolved independently from...
We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using northern European discovery set 835 cases and 5159 controls. A region on chromosome 12q24 was (P = 1.4 × 10−7) replicated convincingly 3.9 10−5) in 798 2931 controls [per allele odds ratio (OR) 1.27 replication cohort, P 7.7 10−11 combined populations]. Single nucleotide polymorphisms the glypican 5 gene 13q32 were also 1.7 1.2 789 2927 (per OR 1.31 3.03 populations). Four...
The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt-Oram syndrome (also known as hand-heart syndrome) and early onset of atrial fibrillation. Revealing how an altered key developmental modulates cardiac physiology vivo will provide unique insights into the mechanisms underlying fibrillation these patients.We analyzed ECGs extended family pedigree patients. Next, we introduced TBX5-p.G125R mouse genome (Tbx5G125R) performed electrophysiologic analyses...
Previously, autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT [1]) was mapped to chromosome 1q42-43 with identification of pathogenic mutations in RYR2. Autosomal recessive CPVT (2) 1p13-21, leading the CASQ2. In this study, we aimed elucidate clinical phenotypes a new variant (3) an inbred Arab family and also delineate chromosomal location gene causing (3).In highly family, symptoms appeared early childhood (7-12 years) three four cases, first appearance turned...
Tetralogy of Fallot (TOF) (OMIM #187500) is the most frequent conotruncal congenital heart defect (CHD) with a range intra‐ and extracardiac phenotypes. TBX5 transcription factor well‐defined roles in forelimb development, mutations are associated Holt–Oram syndrome (HOS) (OMIM#142900). Here we report on screening 94 TOF patients for TBX5, NKX2.5 GATA4 genes. We identified two heterozygous . One mutation was detected Moroccan patient TOF, large ostium secundum atrial septal complete...
It has been well established that histone and DNA modifications are critical to maintaining the equilibrium between pluripotency differentiation during early embryogenesis. Mutations in key regulators of methylation have shown balance gene regulation function is neural development years life. However, there no identified cases linking epigenetic aberrant human fetal demise. Here, we demonstrate a homozygous inactivating mutation deacetylase SIRT6 results severe congenital anomalies perinatal...
Pediatric cranial radiotherapy (CrRT) markedly increases risk of meningiomas. We studied meningioma factors with emphasis on independent and joint effects CrRT dose, exposed volume, exposure age, chemotherapy.The Dutch Cancer Oncology Group-Long-Term Effects after Childhood (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 1963-2001. Histologically confirmed benign meningiomas identified from the population-based Pathology Registry (PALGA;...
Background Three quarters of patients with 22q11.2 Deletion Syndrome (22q11.2DS) have congenital heart disease (CHD), typically conotruncal defects. Although it is currently common practice to test all children typical CHD for 22q11.2DS, many adult not been tested in the past and therefore 22q11.2DS might be under-recognised adults. Objectives To determine prevalence adults tetralogy Fallot (TOF) pulmonary atresia (PA)/ventricular septal defect (VSD) assess level recognition syndrome...
The T gene (brachyury gene) is the founding member of T-box family transcription factors and vital for formation differentiation mesoderm axial development all vertebrates.We report here on four patients from three consanguineous families exhibiting sacral agenesis, a persistent notochordal canal abnormal ossification vertebral bodies, identification characterisation their underlying genetic defect. Given nature similarity phenotypes between families, we performed homozygosity mapping...
Mammals and birds have a specialized cardiac atrioventricular conduction system enabling rapid activation of both ventricles. This may evolved together with high heart rates to support their endothermic state (warm-bloodedness) is seemingly lacking in ectothermic vertebrates from which first mammals then independently evolved. Here, we studied the crocodiles (Alligator mississippiensis), only full ventricular septum. We identified homologues mammalian markers (Tbx3-Tbx5, Scn5a, Gja5,...
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by progressive fibro-fatty myocardial replacement, ventricular arrhythmia, heart failure, and sudden death. Causative mutations can be identified in 60% of patients, most them are found genes encoding mechanical junction proteins the intercalated disk.Whole-exome sequencing was performed on proband ACM family. Sanger used to screen for tight protein 1 ( TJP1) gene unrelated patients. Predictions local structure...
Myocardin (MYOCD) is the founding member of a class transcriptional coactivators that bind serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac development. Insights into molecular functions MYOCD have been obtained from cell culture studies, date, knowledge about vivo roles comes exclusively experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance pathogenic variants. This manifested as...