Genetic Determinants of Heart Rhythm and Conduction Disorders

Het risico op plotse hartdood is deels genetisch bepaald en het identificeren van de componenten die bijdragen aan dit risico kan nieuwe inzichten geven in de mechanismen die ten grondslag liggen aan het ontstaan van ventriculaire ritmestoornissen. De onderliggende oorzaken van plotse hartdood zijn zeer divers van aard. Dit is een van de redenen om de kwantitatieve risicofactoren te bestuderen. Voor plotse hartdood zijn enkele van deze risicofactoren te meten op het elektrocardiogram, namelijk: 1) het QT interval [elektrisch herstel van de hartkamers], 2) het RR interval [hartfrequentie] en 3) de QRS duur [elektrische activatie van de hartkamers]. De doelstellingen van dit proefschrift waren: 1) het bestuderen van de associatie tussen het NOS1AP gen en QT interval/plotse hartdood, 2) door middel van genoomwijde associatie studies de genetische varianten onderliggend aan de genetische bepaalde variatie tussen individuen van de kwantitatieve risicofactoren van plotse hartdood te identificeren, 3) nieuwe methoden te ontwikkelen om ons vermogen hiertoe te vergroten, en 4) het verrichten van gen-medicatie interactie studies. De beschreven studies zijn verricht binnen de Erasmus Rotterdam Gezondheids Onderzoek (ERGO) studie, vaak in nauwe samenwerking met andere studies

Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology

Advances in next-generation sequencing (NGS) techniques, including whole exome sequencing, have facilitated cost-effective sequencing of large regions of the genome, enabling the implementation of NGS in clinical practice. Chronic kidney disease (CKD) is a major contributor to global burden of disease and is associated with an increased risk of morbidity and mortality. CKD can be caused by a wide variety of primary renal disorders. In about one in five CKD patients, no primary renal disease diagnosis can be established. Moreover, recent studies indicate that the clinical diagnosis may be incorrect in a substantial number of patients. Both the absence of a diagnosis or an incorrect diagnosis can have therapeutic implications. Genetic testing might increase the diagnostic accuracy in patients with CKD, especially in patients with unknown etiology. The diagnostic utility of NGS has been shown mainly in pediatric CKD cohorts, while emerging data suggest that genetic testing can also be a valuable diagnostic tool in adults with CKD. In addition to its implications for unexplained CKD, NGS can contribute to the diagnostic process in kidney diseases with an atypical presentation, where it may lead to reclassification of the primary renal disease diagnosis. So far, only a few studies have reported on the diagnostic yield of NGS-based techniques in patients with unexplained CKD. Here, we will discuss the potential diagnostic role of gene panels and whole exome sequencing in pediatric and adult patients with unexplained and atypical CKD

Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update

A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of

Fabry disease with atypical phenotype identified by massively parallel sequencing in early-onset kidney failure

Background. The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%–56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD. Results. In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype. Conclusion. These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure.</p

Fabry disease with atypical phenotype identified by massively parallel sequencing in early-onset kidney failure

Background. The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%–56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD. Results. In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype. Conclusion. These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure.</p

Diagnostic yield of massively parallel sequencing in patients with chronic kidney disease of unknown etiology:rationale and design of a national prospective cohort study

INTRODUCTION: Chronic kidney disease (CKD) can be caused by a variety of systemic or primary renal diseases. The cause of CKD remains unexplained in approximately 20% of patients. Retrospective studies indicate that massively parallel sequencing (MPS)-based gene panel testing may lead to a genetic diagnosis in 12%–56% of patients with unexplained CKD, depending on patient profile. The diagnostic yield of MPS-based testing in a routine healthcare setting is unclear. Therefore, the primary aim of the VARIETY (Validation of algoRithms and IdEnTification of genes in Young patients with unexplained CKD) study is to prospectively address the diagnostic yield of MPS-based gene panel testing in patients with unexplained CKD and an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) before the age of 50 years in clinical practice. METHODS AND ANALYSIS: The VARIETY study is an ongoing, prospective, nationwide observational cohort study to investigate the diagnostic yield of MPS-based testing in patients with unexplained CKD in a routine healthcare setting in the Netherlands. Patients are recruited from outpatient clinics in hospitals across the Netherlands. At least 282 patients will be included to meet the primary aim. Secondary analyses include subgroup analyses according to age and eGFR at first presentation, family history, and the presence of extrarenal symptoms. ETHICS AND DISSEMINATION: Ethical approval for the study has been obtained from the institutional review board of the University Medical Center Groningen. Study findings should inform physicians and policymakers towards optimal implementation of MPS-based diagnostic testing in patients with unexplained CKD

CYP1A2 and coffee intake and the modifying effect of sex, age, and smoking

Background: The enzyme CYP1A2 (cytochrome 1A2) is involved in the metabolism of certain drugs and caffeine, and its activity can be influenced by factors such as sex, age, and smoking. The single nucleotide polymorphism (SNP) rs762551A>C, which has also been studied for its modifying effect on cardiovascular disease, has been reported to alter enzyme activity. Objective: The objective was to study the effect of CYP1A2, sex, age, and smoking on coffee intake. Design: Within the Rotterdam Study, a population-based cohort, all coffee drinkers for whom genome-wide association data were available were selected. Because SNP rs762551 was not on the Illumina 550 platform, SNP rs2472299 was used as a proxy, with the A allele of rs762551 linked to the G allele of rs2472299. Linear regression analyses were used to determine the effect and interaction of rs2472299, sex, age, and smoking on coffee intake. Adjusted geometric means of coffee intake were calculated per genotype for the different smoking and sex strata by using multivariable general linear models. A combined analysis, with the use of a "risk score,"was performed to determine the contribution of each separate factor. Results: rs2472299G>A, female sex, and nonsmoking were significantly inversely related to coffee intake. Coffee intake was lowest in nonsmoking women homozygous for rs2472299G>A (3.49 cups/d; ∼436 mL). All factors contributed almost linearly to the intake of coffee, with the highest coffee intake in smoking men without the A allele (5.32 cups/d; ∼665 mL). Conclusion: rs2472299G>A, linked to rs762551A>C, sex, age, and smoking significantly contribute to coffee intake

Corrigendum: Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages

Cardiolog