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Deep familial phenotyping and genotyping to resolve phenotypic variability of inherited pathogenic genetic variants KU Leuven

The high burden of de novo pathogenic genetic variants in sporadic patients with rare developmental disorders (DD) has led to a de novo paradigm in genetic research and diagnostics. Genetic variants inherited from an unaffected parent are typically disregarded in variant interpretation pipelines. However, we are confronted with a growing list of rare inherited variants, that are enriched in patient versus control cohorts. Mechanisms underlying ...

Development of an innovative hiPSC-derived cardiac-microtissue-based functional assay to determine the pathogenicity of genetic variants with uncertain significance identified in patients with inherited cardiac arrhythmia; University of Antwerp

Maaike Alaerts

Medical Genetics (MEDGEN)

Inherited Cardiac Arrhythmia (ICA) refers to a group of genetic disorders in which patients present with abnormal and potentially harmful heart rhythm. These episodes often go unnoticed, but can lead to sudden cardiac death. At present, over 60 ICA genes have been identified. Using novel next-generation sequencing technology it is possible to screen all ICA genes in a single molecular diagnostic test. This analysis allows the identification of ...

Chromatin structure analysis of rare likely pathogenic inherited Copy Number Variants KU Leuven

Catia Attanasio

Laboratory of Gene Regulation and Disease, Department of Human Genetics

Chromatin structure has been shown to play important roles in the orchestration of gene expression programs during development. Spatio-temporal specific cis-regulatory sequences often lie at a long distance from the gene(s) they regulate, requiring spatial chromatin folding to move them in close proximity of their target promoters and fine-tune the time, place and level of gene expression. Interestingly, several whole-genome chromatin ...

Inherited cardiac arrhythmias: identification of novel genes and development of a new diagnostic tool for translating genetic diagnosis into precision medicine. University of Antwerp

Bart Loeys

Molecular, Cellular and Network Excitability (MCNE), Cardiovascular diseases (CARDIOVASC), Translational Pathophysiological Research (TPR), Molecular biophysics, physiology and pharmacology, Medical Genetics (MEDGEN)

Inherited cardiac arrhythmias (ICA) are a group of predominantly autosomal dominant disorders characterized by a disturbed cardiac action potential that can lead to sudden cardiac death at a young age. Although currently more than 50 genes have been associated with ICA, in roughly 70% of the patients the precise genetic cause is still unknown. Moreover, this group of diseases is genetically and phenotypically heterogeneous and in a molecular ...

New perspectives on familial clustering of Alzheimer's disease: the role of rare genetic risk variants. University of Antwerp

Kristel Sleegers

VIB CMN - Neurodegenerative Brain Diseases Group

Alzheimer's disease (AD) is an important threat to both personal and publich health. Familial clustering of AD has long been known, and in the past few decades, important progress has been made in unraveling the genetics of AD. For patients and their relatives today, the most tangible benefit of this progress is the ability to genetically diagnose or predict the disease. Nevertheless, this only applies to a minority of families, in which a ...

Development of a novel transgenic zebrafish model to determine the pathogenicity of genetic variants for cardiac arrhythmia. University of Antwerp

Dorien Schepers

Molecular, Cellular and Network Excitability (MCNE), Medical Genetics (MEDGEN)

Inherited Cardiac Arrhythmia (ICA), such as long QT syndrome (LQTS) and Brugada syndrome (BrS), refers to a group of hereditary disorders in which patients present with irregular heart rhythm, caused by altered cardiac electrical dynamics. These episodes can remain asymptomatic, but also lead to sudden syncope and sudden death of the individual. Up to date, over 50 different genes have been identified that can cause ICA. Thanks to the advent of ...

Elucidating the pathogenicity of genetic variants of uncertain significance in Brugada syndrome patients by functional modelling in hiPSC-derived cardiomyocytes and zebrafish. University of Antwerp

Bart Loeys

Molecular, Cellular and Network Excitability (MCNE), Aarhus University, Medical Genetics (MEDGEN)

Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels result in detection of numerous genetic "Variants of Uncertain Significance" (so called VUS), but ...

Functional assessment of cis-regulatory elements of inherited retinal diseases (IRDs) in Xenopus tropicalis Ghent University

Kris Vleminckx

Department of Biomedical molecular biology

Non-coding variants in functional genomic regions such as cis-regulatory elements (CREs) may be implicated in missing heritability of inherited retinal diseases (IRDs). We aim to generate a regulatory map of the genome in retina and perform functional studies of (likely) pathogenic variants of CREs associated with IRD genes in Xenopus tropicalis using transgenic reporters and CRISPR/Cas9 genome editing.

Tackling the missing heritability of inherited peripheral neuropathies: towards improved patient care, better mechanistic insights and identification of determinants driving phenotypic diversity. University of Antwerp

Jonathan Baets

Translational Neurosciences (TNW), Neurogenetics Group

Inherited Peripheral Neuropathies (IPN) constitute a large and diverse group of disorders causing length-dependent neurodegeneration of axons in the peripheral nervous system (PNS). As many other neuromuscular disorders, IPN are chronic, debilitating and in some instances life-threatening conditions resulting in tremendous disease burden for patients and society. Affecting 1 in 2500 individuals, IPN share the challenges common to other 'rare ...

Unraveling defects in the human innate immune response: Diagnosis of inherited disorders in the NF-κB pathway KU Leuven

Xavier Bossuyt

Clinical and Diagnostic Immunology, Inborn Errors of Immunity, Adaptive Immunology

Primary immunodeficiencies are inherited diseases that predispose children and adults to recurrent bacterial, viral, and/or fungal infections. The awareness for primary immunodeficiencies is still limited in routine clinical practice and many patients are diagnosed too late to prevent life-threatening infections by appropriate therapy. Toll-like/IL-1R (TIR) receptors and the associated NF-κB signaling pathway are important mediators of the ...

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