Bart Loeys

• University of Antwerp

DDX3X -related neurodevelopmental disorder is one of the most common monogenic causes of intellectual disability in females, with currently >1000 females diagnosed worldwide. In contrast, reports on affected males with DDX3X variants are scarce. The limited knowledge on this X-linked disorder in males hinders the interpretation of hemizygous DDX3X...

Background Individuals harbouring SMAD3 pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in SMAD3- variant-harbouring patients. Methods We analysed two large pedigrees co...

Background In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clini...

ESC Guidelines provide best practice, evidence-based recommendations for diagnosing and treating patients with cardiovascular diseases. It is not always possible for best practices to be followed, however, particularly in low-resource settings. To address this issue, a set of guideline-related documents were created to identify key priorities for u...

In the modern era, cardiologists managing patients and families with cardiomyopathies need to be familiar with every stage of the diagnostic pathway from clinical phenotyping to the prescription and interpretation of genetic tests. This clinical consensus statement from the ESC Council for Cardiovascular Genomics aims to promote the integration of...

Structural variants (SVs) are important contributors to human disease. Their characterization remains however difficult due to their size and association with repetitive regions. Long-read sequencing (LRS) and optical genome mapping (OGM) can aid as their molecules span multiple kilobases and capture SVs in full. In this study, we selected six indi...

Advanced data-driven methods can outperform conventional features in electrocardiogram (ECG) analysis, but often lack interpretability. The variational autoencoder (VAE), a form of unsupervised machine learning, can address this shortcoming by extracting comprehensive and interpretable new ECG features. Our novel VAE model, trained on a dataset com...

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). We created isogenic human induced plur...

Structural variants (SVs) are important contributors to human disease. Their characterization remains however difficult due to their size and association with repetitive regions. Long-read sequencing (LRS) and optical genome mapping (OGM) can aid as their molecules span multiple kilobases and capture SVs in full. In this study, we selected six indi...

Background Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have als...

BACKGROUND Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration. Gain-of-function (GOF) variants in FLNA are associated with oto-palato-digital spectrum disorders (OPDSD). Loss-of-function (LOF) variants give rise to a wide variety of symptoms with periventricular nodular heterotopia (PVNH) and epile...

Background Variants in the MYBPC3 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 MYBPC3 (del exon 23-26) in several probands. We aim...

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (A...

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 ge...

BACKGROUND Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1 . The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch...

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation anal...

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. E...

Background SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patien...

Introduction Loeys-Dietz Syndrome (LDS) is an autosomal dominant connective tissue disorder presenting with thoracic aortic aneurysm and dissection (TAAD). Remarkably, some LDS patients remain cardiovascularly unaffected throughout life, while others carrying the exact same genetic variant die early because of an aortic dissection. We hypothesize t...

Introduction Thoracic aortic aneurysm and dissection (TAAD) is a hallmark of Loeys-Dietz syndrome (LDS) and a prominent cause of morbidity and sudden death. Current drug therapies are only able to slow down but not stop or reverse aneurysm formation. TAAD pathomechanisms remain largely elusive, complicating the development of more effective treatme...

Background: TGFB3 variants cause Loeys–Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical f...

Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective: To identify a new gene for nsBAV. Design, setting, and partic...

The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the ‘Rareservoir’, containing the rare variant ge...

Patients carrying IPO8 bi-allelic loss-of-function variants have a highly consistent phenotype that resembles the phenotype of Loeys-Dietz syndrome. They present with early onset thoracic aortic aneurysm (TAA) and connective tissue findings such as arachnodactyly and joint hypermobility. Other recurrent phenotypic manifestations include facial dysm...

Marfan syndrome (MFS) is a connective tissue disorder with pleiotropic manifestations in the ocular, skeletal and cardiovascular system; and is typically cause by pathogenic variants in the fibrillin-1 (FBN1) gene. We report a generated induced pluripotent cell (iPSC) line of a MFS patient with an FBN1 c.7754T > C (p.Ile2585Thr) variant. The cell l...

Spondyloepiphyseal dysplasia congenita (SEDC) is a severe non-lethal type 2 collagenopathy caused by pathogenic variants in the COL2A1 gene, which encodes the alpha-1 chain of type II collagen. SEDC is clinically characterized by severe short stature, degenerative joint disease, hearing impairment, orofacial anomalies and ocular manifestations. To...

Purpose of review: Structural genomic variants have emerged as a relevant cause for several disorders, including intellectual disability, neuropsychiatric disorders, cancer and congenital heart disease. In this review, we will discuss the current knowledge about the involvement of structural genomic variants and, in particular, copy number variant...

Marfan syndrome (MFS) is a connective tissue disorder with pleiotropic manifestations in the ocular, skeletal and cardiovascular system. Ruptured aortic aneurysms in MFS patients are associated with high mortality rates. MFS is typically caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Here, we report a generated induced pluripotent ce...

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. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on...

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...

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 iPS...

Open in new tabDownload slide Schematic overview of the different important endothelial signaling pathways and molecular processes involved in the pathogenesis of thoracic aortic aneurysm and dissection

Hemizygous missense variants in the X-linked BGN gene, encoding the extracellular matrix protein biglycan, cause spondyloepimetaphyseal dysplasia (SEMD, biglycan type), which is clinically characterized by short stature, brachydactyly and osteoarthritis. Little is known about the pathomechanisms underlying SEMD, biglycan type. IPSC-derived chondroc...

Although standards and guidelines for the interpretation of variants identified in genes that cause Mendelian disorders have been developed, this is not the case for more complex genetic models including variant combinations in multiple genes. During a large curation work conducted on 318 research articles presenting oligogenic variant combinations...

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. Here, we introduce a...

Objective Thoracic Aortic Aneurysm & Dissection (TAAD) can arise at any time without previous warnings and with fatal consequences. We seek to determine the genetic cause of TAAD in a UK multi-generational Caucasian family. Approach Whole exome sequencing was performed and analysed on three affected individuals. Both in vitro and in vivo studies e...

We report a case of a fatal retrograde Type A aortic dissection following thoracic endovascular aortic repair (TEVAR). The patient was diagnosed with vascular Ehlers-Danlos syndrome (vEDS) only postoperatively, which is a relative contraindication for TEVAR. The patient had no major or minor criteria for vEDS. This case report emphasizes pitfalls o...

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS‐related height increase across populations. Height and weight data of individuals wit...

SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, SMAD6-deficiency has been associated with three distinctive human congenital conditions, i.e., congenital heart diseases, including left ventricular obstruction and conotruncal defects, craniosynostosis and radioulnar synostosis. Intrigui...

Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth musc...

Background Timely diagnosis of patients with Heritable Thoracic Aortic Diseases (HTAD) is essential to avoid (often fatal) aortic dissection. Experts of the HTAD rare disease working group of the European Reference Network of Rare Vascular diseases (vascern) aimed to propose a pathway to: (1) improve patient care by diminishing time to diagnosis; (...

Background Since the association of a chromosomal risk haplotype harboring dipeptidyl peptidase-like protein-6 (DPP6) to familial idiopathic ventricular fibrillation (iVF), a growing number of DPP6 missense variants has been reported in patients with ventricular tachyarrhythmias. The mechanisms underlying DPP6 mediated-arrhythmogenesis are not yet...

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.Arg287Gln variant. Peripheral blood mononuclear cells were reprogramme...

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder presenting with a variety of cardiovascular, skeletal, craniofacial and cutaneous manifestations. Aortic rupture or dissection of a thoracic aortic aneurysm (TAA) is the most life-threatening complication. We generated a an iPSC line from peripheral mononuclear blood cel...

Sports Cardiology practice commonly involves the evaluation of athletes for genetically determined cardiac conditions that may predispose to malignant arrhythmias, heart failure, and sudden cardiac death. High-level exercise can lead to electrical and structural cardiac remodelling which mimics inherited cardiac conditions (ICCs). Differentiation b...

Purpose Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies. Methods Index patients and relatives with a P/LP variant in ACTA2 were included. Data were...

Genetic predisposition and risk factors such as hypertension and smoking can instigate the development of thoracic aortic aneurysm (TAA), which can lead to highly lethal aortic wall dissection and/or rupture. Monogenic defects in multiple genes involved in the elastin-contractile unit and the TGFβ signaling pathway have been associated with TAA in...

Introduction The diagnosis of Ehlers-Danlos syndrome is usually based on well-defined diagnostic criteria and the result of DNA investigation. Classical (cEDS) and vascular type (vEDS) are the most prevalent subtypes and are caused by heterozygous pathogenic variants in COL5A1, COL5A2, COL1A1 or, respectively, in COL3A1. We describe 3 cases with co...

Pathogenic variants in JAG1 are known to cause Alagille syndrome (ALGS), a disorder that primarily affects the liver, lung, kidney and skeleton. Whereas cardiac symptoms are also frequently observed in ALGS, thoracic aortic aneurysms have only been reported sporadically in post‐mortem autopsies. We here report two families with segregating JAG1 var...

Vascular Ehlers Danlos syndrome (vEDS) is a rare genetic disorder clinically characterized by vascular, intestinal and uterine fragility and caused by heterozygous pathogenic variants in the COL3A1 gene. Management of patients with vEDS is difficult due to the unpredictability of the events and clear recommendations on the care of adults and childr...

The genetic aetiologies of more than half of rare diseases remain unknown ¹ . Standardised genome sequencing (GS) and phenotyping of large patient cohorts provides an opportunity for discovering the unknown aetiologies ² , but this depends on efficient and powerful analytical methods ³ . We have developed a portable computational and statistical fr...

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation - Flanders (FWO) Introduction SCN5A encodes the α-subunit of voltage-gated cardiac sodium channel Nav1.5. Mutations in SCN5A are identified in about 20% of patients with Brugada syndrome (BrS), an inherited cardiac...

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1.Flanders Research Foundation- FWO (doctoral research grant) 2.UZA Foundation-Wolvenbos Grant 2019 Background Anthracycline chemotherapy is a cornerstone in the treatment of several malignancies. However, it causes substantial toxicit...

Purpose CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 m...

The class I small leucine-rich proteoglycan biglycan is a crucial structural extracellular matrix component that interacts with a wide range of extracellular matrix molecules. In addition, biglycan is involved in sequestering growth factors such as TGF-β and BMPs and thereby regulating pathway activity. Biglycan consists of a 42-kDa core protein li...

Different pathogenic variants in the fibrillin‐1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints and hypermuscularit...

Background The importance of genetic testing for cardiomyopathies has increased in the last decade. However, in heart transplant patients with former cardiomyopathy, genetic testing in retrospect is not routinely performed. We hypothesize that the yield of genetic testing in this population is considerable, and will have a major impact for both pat...

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and ident...

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 r...

Purpose of the review: Thoracic aortic aneurysms and dissections (TAADs) are a major health problem in the Western population. This review summarises recent discoveries in the genetic landscape of TAAD disease, discusses current challenges in clinical practice, and describes the molecular road ahead in TAAD research. Disorders, in which aneurysmal...

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 pro...

Pathogenic variants in JAG1 are known to cause Alagille syndrome (ALGS), a disorder that primarily affects the liver, lung, kidney and skeleton. Whereas cardiac symptoms are also frequently observed in ALGS, thoracic aortic aneurysms have only been reported sporadically in post-mortem autopsies. We here report two families with segregating JAG1 var...

The induced pluripotent stem cell (iPSC) technology allows pathomechanistic and therapeutic investigation of human heritable disorders affecting tissue types whose collection from patients is difficult or even impossible. Amongst them are cartilage diseases. Over the past decade, iPSC‐chondrocyte disease models have been shown to exhibit several ke...

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. Here we report two iPSC lines (BBANTWi006-A, BBANTWi007-A) of a brother and a sister carrying an SCN5A mutation (c.4813+3_4813+6dupGGGT) causing B...

Background Bicuspid aortic valve (BAV) is the most common congenital heart disease, often associated with valve dysfunction, coarctation of the aorta (CoA) and ascending aorta dilatation. Aortic dilatation may result from abnormal regional hemodynamics or inherent vascular disease. Vascular function in pediatric BAV remains poorly characterized. M...

This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant...

Purpose In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were r...

Loeys-Dietz syndrome is an autosomal dominant aortic aneurysm syndrome characterized by multisystemic involvement. The most typical clinical triad includes hypertelorism, bifid uvula or cleft palate and aortic aneurysm with tortuosity. Natural history is significant for aortic dissection at smaller aortic diameter and arterial aneurysms throughout...

Meester-Loeys syndrome is an X-linked form of syndromic thoracic aortic aneurysm, characterized by the involvement of multiple organ systems. More specifically, the cardiovascular, skeletal, craniofacial, cutaneous and neurological systems are affected. Clear clinical overlap with Marfan syndrome and Loeys-Dietz syndrome is observed. Aortic dissect...

In the last years, the field of inheritable ventricular arrhythmia disease modelling has changed significantly with a push towards the use of novel cellular cardiomyocyte based models. However, there is a growing need for new in vivo models to study the disease pathology at the tissue and organ level. Zebrafish provide an excellent opportunity for...

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 i...

Background: SARS-CoV-2 infection induces mucin overexpression further promoting disease. As mucins are critical components of the innate immunity, unravelling their expression profiles that dictate the course of disease could greatly enhance our understanding and management of COVID-19. Methods: Using validated RT-PCR assays, we assessed mucin m...

Background Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. Methods We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a...

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. Here we present a proband who experienced SCD in his...

Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX vari...

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...

Background Aortic root dilation is a major complication of Marfan syndrome and is one of the most important criteria in establishing the diagnosis. Currently, different echocardiographic nomograms are used to calculate aortic root Z-scores. The aim of the present study was to assess the potential differences in aortic root measurements when aortic...

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that...

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 mimic...

Loeys–Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder, first described in 2005. It is characterized by widespread arterial tortuosity and aneurysmal disease in addition to a variety of skeletal (e.g., pectus excavatum or carinatum, scoliosis, camptodactyly, arachnodactyly), craniofacial (e.g., hypertelorism, bifid uvula...