Generation of four distinct isogenic cell lines with truncating variants in I-band or A-band titin.

Truncating variants in TTN (TTNtv) are present in 15-25 % of patients with idiopathic dilated cardiomyopathy. Interestingly, the pathogenicity of TTNtv seems to be linked to their location within the gene. More proximal I-band TTNtv (TTNtvI) harbour less pathogenic potential than distant A-band TTNtv (TTNtvA).

Phenotypic spectrum of the first Belgian founder: a large multi-exon deletion with a varying phenotype.

Background: Variants in the gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in (del exon 23-26) in several probands.

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: State-of-the-Art Review.

Close monitoring for cardiotoxicity during anthracycline chemotherapy is crucial for early diagnosis and therapy guidance. Currently, monitoring relies on cardiac imaging and serial measurement of cardiac biomarkers like cardiac troponin and natriuretic peptides. However, these conventional biomarkers are nonspecific indicators of cardiac damage.

Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study.

Background: Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking.

Methods: We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography).

iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development.

With the discovery of induced pluripotent stem cell (iPSCs) a wide range of cell types, including iPSC-derived cardiomyocytes (iPSC-CM), can now be generated from an unlimited source of somatic cells. These iPSC-CM are used for different purposes such as disease modelling, drug discovery, cardiotoxicity testing and personalised medicine. The 2D iPSC-CM models have shown promising results, but they are known to be more immature compared to in vivo adult cardiomyocytes.

Clinical and functional characterisation of a recurrent KCNQ1 variant in the Belgian population.

Background: The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital.

Improved selection of zebrafish CRISPR editing by early next-generation sequencing based genotyping.

Despite numerous prior attempts to improve knock-in (KI) efficiency, the introduction of precise base pair substitutions by the CRISPR-Cas9 technique in zebrafish remains challenging. In our efforts to generate KI zebrafish models of human CACNA1C mutations, we have tested the effect of several CRISPR determinants on KI efficiency across two sites in a single gene and developed a novel method for early selection to ameliorate KI efficiency. We identified optimal KI conditions for Cas9 protein and non-target asymmetric PAM-distal single stranded deoxynucleotide repair templates at both cacna1c sites.

Invasiveness potential of pneumococcal serotypes in children after introduction of PCV13 in Blantyre, Malawi.

Introduction: The introduction of PCV13 to the Malawi infant immunization schedule in 2011 has been associated with reduced disease from Streptococcus pneumoniae. Improved understanding of serotypes with high invasive potential can guide future vaccination interventions. We aimed to estimate pneumococcal serotypes associated with acute respiratory infection (ARI) and invasive pneumococcal disease (IPD) in hospitalized children in Blantyre, Malawi.

varAmpliCNV: analyzing variance of amplicons to detect CNVs in targeted NGS data.

Motivation: Computational identification of copy number variants (CNVs) in sequencing data is a challenging task. Existing CNV-detection methods account for various sources of variation and perform different normalization strategies. However, their applicability and predictions are restricted to specific enrichment protocols.

Generation and validation of an iPSC line (BBANTWi008-A) from a Loeys-Dietz Syndrome type 3 patient.

Loeys-Dietz Syndrome (LDS) is an autosomal dominant connective tissue disorder. The major hallmark of LDS is thoracic aortic aneurysm and dissection (TAAD). We generated an induced pluripotent stem cell (iPSC) line of a severely affected LDS patient carrying a pathogenic SMAD3 p.

Luminescent Human iPSC-Derived Neurospheroids Enable Modeling of Neurotoxicity After Oxygen-glucose Deprivation.

Despite the considerable impact of stroke on both the individual and on society, a neuroprotective therapy for stroke patients is missing. This is partially due to the current lack of a physiologically relevant human in vitro stroke model. To address this problem, we have developed a luminescent human iPSC-derived neurospheroid model that enables real-time read-out of neural viability after ischemia-like conditions.

Generation of two induced pluripotent stem cell (iPSC) lines (BBANTWi006-A, BBANTWi007-A) from Brugada syndrome patients carrying an SCN5A mutation.

Brugada syndrome (BrS) is an inherited primary electrical disorder of the heart. 25% of BrS patients carry a mutation in the SCN5A gene, encoding the cardiac specific voltage-gated sodium channel Nav1.5.

Morpho-functional comparison of differentiation protocols to create iPSC-derived cardiomyocytes.

Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) offer an attractive platform for cardiovascular research. Patient-specific iPSC-CMs are very useful for studying disease development, and bear potential for disease diagnostics, prognosis evaluation and development of personalized treatment. Several monolayer-based serum-free protocols have been described for the differentiation of iPSCs into cardiomyocytes, but data on their performance are scarce.

Two novel presentations of KCNMA1-related pathology--Expanding the clinical phenotype of a rare channelopathy.

Background: KCNMA1 mutations have recently been associated with a wide range of dysmorphological, gastro-intestinal, cardiovascular, and neurological manifestations.

Methods: Whole exome sequencing was performed in order to identify the underlying pathogenic mutation in two cases presenting with diverse phenotypical manifestations that did not fit into well-known clinical entities.

Results: In an 8-year-old boy presenting with severe aortic dilatation, facial dysmorphism, and overgrowth at birth a de novo p.

Molecular autopsy and subsequent functional analysis reveal de novo DSG2 mutation as cause of sudden death.

Sudden cardiac death (SCD) is a common cause of death in young adults. In up to 80% of cases a genetic cause is suspected. Next-generation sequencing of candidate genes can reveal the cause of SCD, provide prognostic management, and facilitate pre-symptomatic testing and prevention in relatives.

Impact and effectiveness of 13-valent pneumococcal conjugate vaccine on population incidence of vaccine and non-vaccine serotype invasive pneumococcal disease in Blantyre, Malawi, 2006-18: prospective observational time-series and case-control studies.

Background: The population impact of pneumococcal conjugate vaccines (PCVs) depends on direct and indirect protection. Following Malawi's introduction of the 13-valent PCV (PCV13) in 2011, we examined its impact on vaccine and non-vaccine serotype invasive pneumococcal disease among vaccine-eligible-age and vaccine-ineligible-age children and adults.

Methods: We did a prospective observational time-series analysis and a case-control study.

A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-β protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-β signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes.

iPSC-Cardiomyocyte Models of Brugada Syndrome-Achievements, Challenges and Future Perspectives.

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes.

Clinical characterization of the first Belgian SCN5A founder mutation cohort.

Aims: We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected.

Compound Heterozygous Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report.

Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in the gene, encoding the main cardiac sodium Na1.5 channel.

Cardiogeneticsbank@UZA: A Collection of DNA, Tissues, and Cell Lines as a Translational Tool.

Cardiogeneticsbank@UZA is an academic hospital integrated biobank that collects aortic tissue, blood, cell lines (fibroblasts, vascular smooth muscle cells, peripheral blood mononuclear cells, and induced pluripotent stem cells), and DNA from patients with cardiogenetic disorders, for both diagnostic and research purposes. We adhere to a quality management system and have established standard protocols for the sampling and processing of all cardiogenetic patient related materials. Cardiogeneticsbank@UZA is embedded in the Biobanking and Biomolecular Resources Research Infrastructure Belgium (BBMRI.