Publications by authors named "Bart Loeys"

181 Publications

Comparability of different Z-score equations for aortic root dimensions in children with Marfan syndrome.

Cardiol Young 2021 Apr 12:1-7. Epub 2021 Apr 12.

Department of Pediatric Cardiology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.

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 root Z-scores were obtained in a cohort of paediatric Marfan patients using several published nomograms.

Methods: In a cohort of 100 children with Marfan syndrome, Z-scores for aortic root dimensions were calculated according to the nomograms of Pettersen et al, Gautier et al, Colan et al, and Lopez et al. Bland-Altman plots were used to estimate mean differences in Z-scores and to establish limits of agreement.

Results: The mean Z-score of the sinus of Valsalva for Lopez et al was significantly higher compared to Gautier et al (p < 0.01) and Pettersen et al (p = 0.03). The nomogram of Lopez et al resulted in substantially higher Z-scores in patients with a large sinus of Valsalva diameter. Thirty-five percentage of the studied patients would have a Z-score ≥ 2 using Lopez et al compared to 20% for Pettersen et al, 21% for Gautier et al, and 33% for Colan et al.

Conclusion: The currently available nomograms for calculating Z-scores of aortic dilation in children with Marfan syndrome lead to clinically relevant differences in Z-scores, especially in children with a relative large aortic root diameter. This could have impact on both the diagnosis and treatment of patients with Marfan syndrome.
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http://dx.doi.org/10.1017/S1047951121001311DOI Listing
April 2021

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

Int J Mol Sci 2021 Mar 10;22(6). Epub 2021 Mar 10.

Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium.

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. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias.
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http://dx.doi.org/10.3390/ijms22062825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001521PMC
March 2021

Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Cardiovasc Res 2021 Mar 19. Epub 2021 Mar 19.

Department of Hypertension, National Institute of Cardiology, Warsaw, Poland.

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 the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string of beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research which has led to improved understandings of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.
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http://dx.doi.org/10.1093/cvr/cvab086DOI Listing
March 2021

The resting membrane potential of hSC-CM in a syncytium is more hyperpolarised than that of isolated cells.

Channels (Austin) 2021 Dec;15(1):239-252

Department of Biomedical Sciences, University of Antwerp , Antwerp, Belgium.

Human-induced pluripotent stem cell (hiPSC) and stem cell (hSC) derived cardiomyocytes (CM) are gaining popularity as in vitro model for cardiology and pharmacology studies. A remaining flaw of these cells, as shown by single-cell electrophysiological characterization, is a more depolarized resting membrane potential (RMP) compared to native CM. Most reports attribute this to a lower expression of the Kir2.1 potassium channel that generates the I current. However, most RMP recordings are obtained from isolated hSC/hiPSC-CMs whereas in a more native setting these cells are interconnected with neighboring cells by connexin-based gap junctions, forming a syncytium. Hereby, these cells are electrically connected and the total pool of I increases. Therefore, the input resistance (Ri) of interconnected cells is lower than that of isolated cells. During patch clamp experiments pipettes need to be well attached or sealed to the cell, which is reflected in the seal resistance (Rs), because a nonspecific ionic current can leak through this pipette-cell contact or seal and balance out small currents within the cell such as I. By recording the action potential of isolated hSC-CMs and that of hSC-CMs cultured in small monolayers, we show that the RMP of hSC-CMs in monolayer is approximately -20 mV more hyperpolarized compared to isolated cells. Accordingly, adding carbenoxolone, a connexin channel blocker, isolates the cell that is patch clamped from its neighboring cells of the monolayer and depolarizes the RMP. The presented data show that the recorded RMP of hSC-CMs in a syncytium is more negative than that determined from isolated hSC/hiPSC-CMs, most likely because the active pool of Kir2.1 channels increased.
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http://dx.doi.org/10.1080/19336950.2021.1871815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817136PMC
December 2021

Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing.

Sci Rep 2021 Jan 12;11(1):764. Epub 2021 Jan 12.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Marfan syndrome and related disorders are a group of heritable connective tissue disorders and share many clinical features that involve cardiovascular, skeletal, craniofacial, ocular, and cutaneous abnormalities. The majority of affected individuals have aortopathies associated with early mortality and morbidity. Implementation of targeted gene panel next-generation sequencing in these individuals is a powerful tool to obtain a genetic diagnosis. Here, we report on clinical and genetic spectrum of 53 families from India with a total of 83 patients who had a clinical diagnosis suggestive of Marfan syndrome or related disorders. We obtained a molecular diagnosis in 45/53 (85%) index patients, in which 36/53 (68%) had rare variants in FBN1 (Marfan syndrome; 63 patients in total), seven (13.3%) in TGFBR1/TGFBR2 (Loeys-Dietz syndrome; nine patients in total) and two patients (3.7%) in SKI (Shprintzen-Goldberg syndrome). 21 of 41 rare variants (51.2%) were novel. We did not detect a disease-associated variant in 8 (15%) index patients, and none of them met the Ghent Marfan diagnostic criteria. We found the homozygous FBN1 variant p.(Arg954His) in a boy with typical features of Marfan syndrome. Our study is the first reporting on the spectrum of variants in FBN1, TGFBR1, TGFBR2, and SKI in Indian individuals.
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http://dx.doi.org/10.1038/s41598-020-80755-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804850PMC
January 2021

PTGIR, a susceptibility gene for fibromuscular dysplasia?

Cardiovasc Res 2021 Mar;117(4):990-992

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Belgium.

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http://dx.doi.org/10.1093/cvr/cvaa353DOI Listing
March 2021

Clinical characterization of the first Belgian SCN5A founder mutation cohort.

Europace 2020 Nov 22. Epub 2020 Nov 22.

Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, 2650 Edegem, Belgium.

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.

Methods And Results: The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS.

Conclusion: The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.
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http://dx.doi.org/10.1093/europace/euaa305DOI Listing
November 2020

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

Genet Med 2021 Feb 27;23(2):352-362. Epub 2020 Oct 27.

Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium.

Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit.

Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.

Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly.

Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.
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http://dx.doi.org/10.1038/s41436-020-00981-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862067PMC
February 2021

Delineation of a new fibrillino-2-pathy with evidence for a role of in the pathogenesis of carpal tunnel syndrome.

J Med Genet 2020 Sep 8. Epub 2020 Sep 8.

Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium

Background: Although carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis.

Methods And Results: We report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 () gene that co-segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-β signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%-3.4%, p<0.001) and high-impact (6.9% vs 2.7%, p<0.001) variants in patient alleles compared with controls.

Conclusion: The identification of a novel variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact variants in patients with sporadic CTS, strongly suggest a role of in the pathogenesis of CTS.
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http://dx.doi.org/10.1136/jmedgenet-2020-107085DOI Listing
September 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Authors:
Roddy Walsh Najim Lahrouchi Rafik Tadros Florence Kyndt Charlotte Glinge Pieter G Postema Ahmad S Amin Eline A Nannenberg James S Ware Nicola Whiffin Francesco Mazzarotto Doris Škorić-Milosavljević Christian Krijger Elena Arbelo Dominique Babuty Hector Barajas-Martinez Britt M Beckmann Stéphane Bézieau J Martijn Bos Jeroen Breckpot Oscar Campuzano Silvia Castelletti Candan Celen Sebastian Clauss Anniek Corveleyn Lia Crotti Federica Dagradi Carlo de Asmundis Isabelle Denjoy Sven Dittmann Patrick T Ellinor Cristina Gil Ortuño Carla Giustetto Jean-Baptiste Gourraud Daisuke Hazeki Minoru Horie Taisuke Ishikawa Hideki Itoh Yoshiaki Kaneko Jørgen K Kanters Hiroki Kimoto Maria-Christina Kotta Ingrid P C Krapels Masahiko Kurabayashi Julieta Lazarte Antoine Leenhardt Bart L Loeys Catarina Lundin Takeru Makiyama Jacques Mansourati Raphaël P Martins Andrea Mazzanti Stellan Mörner Carlo Napolitano Kimie Ohkubo Michael Papadakis Boris Rudic Maria Sabater Molina Frédéric Sacher Hatice Sahin Georgia Sarquella-Brugada Regina Sebastiano Sanjay Sharma Mary N Sheppard Keiko Shimamoto M Benjamin Shoemaker Birgit Stallmeyer Johannes Steinfurt Yuji Tanaka David J Tester Keisuke Usuda Paul A van der Zwaag Sonia Van Dooren Lut Van Laer Annika Winbo Bo G Winkel Kenichiro Yamagata Sven Zumhagen Paul G A Volders Steven A Lubitz Charles Antzelevitch Pyotr G Platonov Katja E Odening Dan M Roden Jason D Roberts Jonathan R Skinner Jacob Tfelt-Hansen Maarten P van den Berg Morten S Olesen Pier D Lambiase Martin Borggrefe Kenshi Hayashi Annika Rydberg Tadashi Nakajima Masao Yoshinaga Johan B Saenen Stefan Kääb Pedro Brugada Tomas Robyns Daniela F Giachino Michael J Ackerman Ramon Brugada Josep Brugada Juan R Gimeno Can Hasdemir Pascale Guicheney Silvia G Priori Eric Schulze-Bahr Naomasa Makita Peter J Schwartz Wataru Shimizu Takeshi Aiba Jean-Jacques Schott Richard Redon Seiko Ohno Vincent Probst Elijah R Behr Julien Barc Connie R Bezzina

Genet Med 2021 Jan 7;23(1):47-58. Epub 2020 Sep 7.

Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

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

Front Cardiovasc Med 2020 24;7:117. Epub 2020 Jul 24.

Center of Medical Genetics, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.

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. Here we present a severe case of cardiac sodium channelopathy with BrS caused by compound heterozygous mutations. We performed a genetic analysis of in a male proband who collapsed during cycling at the age of 2 years. Because of atrial standstill, he received a pacemaker, and at the age of 3 years, he experienced a collapse anew with left-sided brain stroke. A later ECG taken during a fever unmasked a characteristic BrS type-1 pattern. The functional effect of the detected genetic variants was investigated. Next-generation sequencing allowed the detection of two variants in : c.4813+3_4813+6dupGGGT-a Belgian founder mutation-and c.4711 T>C, p.Phe1571Leu. A familial segregation analysis showed the presence of the founder mutation in the proband's affected father and paternal aunt and the occurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed a functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the β-subunit. Compared to the wild type, p.Phe1571Leu displayed a hyperpolarizing shift in the voltage dependence of inactivation (loss-of-function), while the activation parameters were unaffected. Using the peptide toxin nemertide α-1, the variant's loss-of-function effect could be restored due to a toxin-dependent reduction of channel inactivation. This is the first report providing support for the pathogenicity of the p.Phe1571Leu variant which, together with the c.4813+3_4813+6dupGGGT founder mutation, explains the severity of the phenotype of cardiac sodium channelopathy with BrS in the presented case.
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http://dx.doi.org/10.3389/fcvm.2020.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396896PMC
July 2020

Biglycan in the Skeleton.

J Histochem Cytochem 2020 11 6;68(11):747-762. Epub 2020 Jul 6.

Molecular Biology of Bones and Teeth Section, National Institutes of Dental and Craniofacial Research, National Institutes of Health, U.S. Department of Health & Human Services, Bethesda, Maryland.

Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of Biglycan and other related SLRPs in mineralizing tissues of the skeleton. The review is divided into sections that include Biglycan's role in structural biology, signaling, craniofacial and long bone homeostasis, remodeled skeletal tissues, and in human genetics. While many cell types in the skeleton are now known to be affected by Biglycan, there are still unanswered questions about its mechanism of action(s).
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http://dx.doi.org/10.1369/0022155420937371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649967PMC
November 2020

Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

J Pediatr 2020 07;222:213-220.e5

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Departments of Pharmacology and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.

Objective: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial.

Study Design: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models.

Results: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status.

Conclusions: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
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http://dx.doi.org/10.1016/j.jpeds.2020.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323908PMC
July 2020

Chondrodysplasias and Aneurysmal Thoracic Aortopathy: An Emerging Tale of Molecular Intersection.

Trends Mol Med 2020 08 5;26(8):783-795. Epub 2020 Jun 5.

Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Although at first glance chondrodysplasia and aneurysmal thoracic aortopathy seem oddly dissimilar, recent lines of evidences indicate that they share molecular similarities. Chondrodysplasias are a group of skeletal disorders characterized by genetic defects in hyaline cartilage. Aneurysmal thoracic aortopathy is the pathological enlargement of the thoracic aorta due to wall weakness, along with its ensuing life-threatening complications (i.e., aortic dissection and/or rupture). Extracellular matrix dysregulation, abnormal TGF-β signaling, and, to a more limited extent, endoplasmic reticulum stress emerge as common disease processes. In this review we provide a comprehensive overview of the genetic and pathomechanistic overlap as well as of how these commonalities can guide treatment strategies for both disease entities.
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http://dx.doi.org/10.1016/j.molmed.2020.05.004DOI Listing
August 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Authors:
Najim Lahrouchi Rafik Tadros Lia Crotti Yuka Mizusawa Pieter G Postema Leander Beekman Roddy Walsh Kanae Hasegawa Julien Barc Marko Ernsting Kari L Turkowski Andrea Mazzanti Britt M Beckmann Keiko Shimamoto Ulla-Britt Diamant Yanushi D Wijeyeratne Yu Kucho Tomas Robyns Taisuke Ishikawa Elena Arbelo Michael Christiansen Annika Winbo Reza Jabbari Steven A Lubitz Johannes Steinfurt Boris Rudic Bart Loeys M Ben Shoemaker Peter E Weeke Ryan Pfeiffer Brianna Davies Antoine Andorin Nynke Hofman Federica Dagradi Matteo Pedrazzini David J Tester J Martijn Bos Georgia Sarquella-Brugada Óscar Campuzano Pyotr G Platonov Birgit Stallmeyer Sven Zumhagen Eline A Nannenberg Jan H Veldink Leonard H van den Berg Ammar Al-Chalabi Christopher E Shaw Pamela J Shaw Karen E Morrison Peter M Andersen Martina Müller-Nurasyid Daniele Cusi Cristina Barlassina Pilar Galan Mark Lathrop Markus Munter Thomas Werge Marta Ribasés Tin Aung Chiea C Khor Mineo Ozaki Peter Lichtner Thomas Meitinger J Peter van Tintelen Yvonne Hoedemaekers Isabelle Denjoy Antoine Leenhardt Carlo Napolitano Wataru Shimizu Jean-Jacques Schott Jean-Baptiste Gourraud Takeru Makiyama Seiko Ohno Hideki Itoh Andrew D Krahn Charles Antzelevitch Dan M Roden Johan Saenen Martin Borggrefe Katja E Odening Patrick T Ellinor Jacob Tfelt-Hansen Jonathan R Skinner Maarten P van den Berg Morten Salling Olesen Josep Brugada Ramón Brugada Naomasa Makita Jeroen Breckpot Masao Yoshinaga Elijah R Behr Annika Rydberg Takeshi Aiba Stefan Kääb Silvia G Priori Pascale Guicheney Hanno L Tan Christopher Newton-Cheh Michael J Ackerman Peter J Schwartz Eric Schulze-Bahr Vincent Probst Minoru Horie Arthur A Wilde Michael W T Tanck Connie R Bezzina

Circulation 2020 Jul 20;142(4):324-338. Epub 2020 May 20.

Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Extracellular Matrix in Vascular Disease, Part 2/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2189-2203

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia. Electronic address:

Medium-sized and large arteries consist of 3 layers: the tunica intima, tunica media, and tunica adventitia. The tunica media accounts for the bulk of the vessel wall and is the chief determinant of mechanical compliance. It is primarily composed of circumferentially arranged layers of vascular smooth muscle cells that are separated by concentrically arranged elastic lamellae; a form of extracellular matrix (ECM). The tunica media is separated from the tunica intima and tunica adventitia, the innermost and outermost layers, respectively, by the internal and external elastic laminae. This second part of a 4-part JACC Focus Seminar discusses the contributions of the ECM to vascular homeostasis and pathology. Advances in genetics and proteomics approaches have fostered significant progress in our understanding of vascular ECM. This review highlights the important role of the ECM in vascular disease and the prospect of translating these discoveries into clinical disease biomarkers and potential future therapies.
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http://dx.doi.org/10.1016/j.jacc.2020.03.018DOI Listing
May 2020

Hide and seek: Somatic SMAD3 mutations in melorheostosis.

J Exp Med 2020 05;217(5)

Center for Medical Genetics, University of Antwerp/Antwerp University Hospital, Antwerp, Belgium.

In the current issue of JEM, Kang et al. (https://doi.org/10.1084/jem.20191499) describe somatic mutations in the SMAD3 gene causing endosteal melorheostosis. Using osteoblast models, the identified mutations are demonstrated to exert a gain-of-function mechanism, augmenting transforming growth factor (TGF) β signaling. These findings provide further insights into the genetic etiology of melorheostosis and consolidate the importance of the TGFβ pathway in skeletal disorders.
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http://dx.doi.org/10.1084/jem.20200185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201934PMC
May 2020

Blood biomarkers in patients with bicuspid aortic valve disease.

J Cardiol 2020 09 4;76(3):287-294. Epub 2020 Apr 4.

Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address:

Background: Patients with a bicuspid aortic valve (BAV) are at risk of developing valve deterioration and aortic dilatation. We aimed to investigate whether blood biomarkers are associated with disease stage in patients with BAV.

Methods: Serum levels of high sensitivity C-reactive protein (hsCRP), high sensitivity troponin T (hsTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and total transforming growth factor-beta 1 (TGF-ß1) were measured in adult BAV patients with valve dysfunction or aortic pathology. Age-matched general population controls were included for TGFß-1 measurements. Correlation analyses and multivariable linear regression were used to determine the association between (2log-transformed) biomarker levels and aortic valve regurgitation, aortic valve stenosis, aortic dilatation, or left ventricular function.

Results: hsCRP and hsTnT were measured in the total group of 183 patients (median age 34 years, 25th-75th percentile 23-46), NT-proBNP in 162 patients, and TGF-ß1 beta in 108 patients. Elevated levels of NT-proBNP were found in 20% of the BAV patients, elevated hsTnT in 6%, and elevated hsCRP in 7%. Higher hsTnT levels were independently associated with aortic regurgitation [odds ratio per doubling (OR) 1.34, 95% CI 1.01;1.76] and higher NT-proBNP levels with aortic valve maximal velocity (ß 0.17, 95%CI 0.07;0.28) and aortic regurgitation (OR 1.41, 95%CI 1.11;1.79). Both BAV patients with (9.9 ± 2.7 ng/mL) and without aortic dilatation (10.4 ± 2.9 ng/mL) showed lower TGF-ß1 levels compared to general population controls (n = 85, 11.8 ± 3.2 ng/mL).

Conclusions: Higher NT-proBNP and hsTNT levels were associated with aortic valve disease in BAV patients. TGF-ß1 levels were lower in BAV patients than in the general population, and not related to aortic dilatation. Longitudinal data are needed to further investigate the prognostic value of biomarkers in these patients.
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http://dx.doi.org/10.1016/j.jjcc.2020.02.023DOI Listing
September 2020

Predictors of Bicuspid Aortic Valve-Associated Aortopathy in Childhood: A Report From the MIBAVA Consortium.

Circ Cardiovasc Imaging 2020 03 17;13(3):e009717. Epub 2020 Mar 17.

Division of Cardiology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Canada (M.G., R.R., C.M., S.M., Ch.-P.S.F., C.M., L.M.).

Background: Bicuspid aortic valve (BAV) is the most prevalent congenital heart defect affecting 1% to 2% of the population. It is associated with ascending aorta dilatation. Valve morphology, aortic stenosis (AS), and aortic insufficiency (AI) have been proposed as potential risk factors; however, evaluating their role is difficult, as these factors are inherently related. The aim of this study was to determine whether BAV morphology and dysfunction are independent determinants for ascending aorta dilatation in pediatric patients.

Methods: A multicenter, retrospective, cross-sectional study of pediatric BAV patients followed since 2004 was performed. Imaging data were assessed for BAV morphology, severity of AS and AI, history of coarctation, and aortic dimensions. Associations were determined using multivariable regression analysis. A subset of patients undergoing aortic interventions (balloon dilation or Ross) were assessed longitudinally.

Results: Data were obtained from 2122 patients (68% male; median age 10.2 years). Fifty percent of patients had ascending aorta dilatation. Right and noncoronary cusp fusion, increasing AS and AI, and older age were independently associated with ascending aorta dilatation. A history of coarctation was associated with less ascending aorta dilatation. In patients with neither AS nor AI, 37% had ascending aorta dilatation (4% severe). No complications related to aortic dilatation occurred in this cohort. Aortic scores were determined, and a -score calculator was created for this population.

Conclusions: In this large pediatric cohort of patients with BAV, valve morphology, AS, and AI are independently associated with ascending aorta dilatation, suggesting that hemodynamic factors influence aortopathy. However, even in BAVs with no AS or AI, there is significant ascending aorta dilatation independent of valve morphology. Interventions that led to changes in degree of AI and AS did not seem to influence change in aortic dimensions. The current BAV cohort can be used as a reference group for expected changes in aortic dimensions during childhood.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.009717DOI Listing
March 2020

A mutation update for the FLNC gene in myopathies and cardiomyopathies.

Hum Mutat 2020 06 20;41(6):1091-1111. Epub 2020 Mar 20.

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.
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http://dx.doi.org/10.1002/humu.24004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318287PMC
June 2020

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants.

Orphanet J Rare Dis 2019 11 21;14(1):264. Epub 2019 Nov 21.

VASCERN HTAD European Reference Centre, Ghent, Belgium.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.
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http://dx.doi.org/10.1186/s13023-019-1186-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868850PMC
November 2019

Progressive Pulmonary Artery Dilatation is Associated with Type B Aortic Dissection in Patients with Marfan Syndrome.

J Clin Med 2019 Nov 2;8(11). Epub 2019 Nov 2.

Department of Cardiology, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.

Objective: Marfan syndrome (MFS) is a connective tissue disorder associated with severe cardiovascular morbidity and mortality. It is unknown if aorta complications in MFS are associated with progressive pulmonary artery (PA) dilatation.

Methods: We measured the PA diameter on routine magnetic resonance imaging in a population of MFS patients seen in our specialised centre with follow up of diameters as well as the outcome.

Results: PA dilatation was defined as an increase in diameter of 2 mm or more, and 71 patients (44%) of our total cohort ( = 162) met this criterion; mean follow up between two scans was 8.6 years (standard deviation (SD) ± 2.7 years). Furthermore, 28 patients suffered from dissections, of which 14 had a type A dissection, 10 had a type B dissection, and 4 patients suffered from both. Of those who suffered from dissection, 64% (18 out of 28) had a dilatation of the PA, versus 39% (53 out of 134) in the patient group without a dissection ( < 0.05). There was a significant association between type B dissection and descending aorta diameter (OR 1.14; 95% CI 1.05-1.24 < 0.01) and PA dilatation (OR 1.69; 95% CI 1.03-2.77 = 0.04). In the multivariable analysis the final model for type B dissection, only systolic blood pressure (OR 1.06; 95% CI 1.01-1.11 = 0.02) and PA dilatation were statistically significant (OR 1.85; 95% CI 1.10-3.12 = 0.02) while descending aorta diameter was not.

Conclusions: We report an association between progressive PA dilatation and type B dissection. Our findings encourage a renewed interest in PA dimensions in MFS.
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http://dx.doi.org/10.3390/jcm8111848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912475PMC
November 2019

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

Front Med (Lausanne) 2019 6;6:198. Epub 2019 Sep 6.

Center of Medical Genetics, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.

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.be) and samples from this biobank are available for commercial and academic researchers, through an established access procedure. Currently, the extremely valuable cardiogenetics collection consists of more than 8,700 DNA samples, 380 tissue samples, and 500 cell lines of 7,578 patients, and is linked with extensive clinical data. Some interesting potential research applications are discussed.
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http://dx.doi.org/10.3389/fmed.2019.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742711PMC
September 2019

Defining the Clinical, Molecular and Ultrastructural Characteristics in Occipital Horn Syndrome: Two New Cases and Review of the Literature.

Genes (Basel) 2019 07 12;10(7). Epub 2019 Jul 12.

Center for Medical Genetics Ghent, Ghent University Hospital, 9000 Ghent, Belgium.

Occipital horn syndrome (OHS) is a rare connective tissue disorder caused by pathogenic variants in ATP7A, encoding a copper transporter. The main clinical features, including cutis laxa, bony exostoses, and bladder diverticula are attributed to a decreased activity of lysyl oxidase (LOX), a cupro-enzyme involved in collagen crosslinking. The absence of large case series and natural history studies precludes efficient diagnosis and management of OHS patients. This study describes the clinical and molecular characteristics of two new patients and 32 patients previously reported in the literature. We report on the need for long-term specialized care and follow-up, in which MR angiography, echocardiography and spirometry should be incorporated into standard follow-up guidelines for OHS patients, next to neurodevelopmental, orthopedic and urological follow-up. Furthermore, we report on ultrastructural abnormalities including increased collagen diameter, mild elastic fiber abnormalities and multiple autophagolysosomes reflecting the role of lysyl oxidase and defective ATP7A trafficking as pathomechanisms of OHS.
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http://dx.doi.org/10.3390/genes10070528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678539PMC
July 2019

Genetic counselling and testing in adults with congenital heart disease: A consensus document of the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics.

Eur J Prev Cardiol 2020 09 11;27(13):1423-1435. Epub 2019 Jun 11.

European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group.

Thanks to a better knowledge of the genetic causes of many diseases and an improvement in genetic testing techniques, genetics has gained an important role in the multidisciplinary approach to diagnosis and management of congenital heart disease and aortic pathology. With the introduction of strategies for precision medicine, it is expected that this will only increase further in the future. Because basic knowledge of the indications, the opportunities as well as the limitations of genetic testing is essential for correct application in clinical practice, this consensus document aims to give guidance to care-providers involved in the follow-up of adults with congenital heart defects and/or with hereditary aortic disease. This paper is the result of a collaboration between the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics. Throughout the document, the importance of correct counseling in the process of genetic testing is emphasized, indications and timing for genetic studies are discussed as well as the technical modalities of genetic testing. Finally, the most important genetic diseases in adult congenital heart disease and aortic pathology are also discussed.
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http://dx.doi.org/10.1177/2047487319854552DOI Listing
September 2020

Arterial Tortuosity.

Hypertension 2019 05;73(5):951-960

Division of Cardiology, Cliniques Universitaires Saint-Luc and Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique (A.P.), Université Catholique de Louvain, Brussels, Belgium.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11647DOI Listing
May 2019

Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.

Eur J Hum Genet 2019 07 28;27(7):1033-1043. Epub 2019 Feb 28.

Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. Based on the presence of overlapping CNVs in patients with cardiovascular phenotypes in the DECIPHER database, the identification of similar CNVs in whole-exome sequencing data of 67 BAV/TAA patients and suggested topological domain involvement from Hi-C data, supportive evidence was obtained for two genes (DGCR6 and TBX20) of the seven initially validated CNVs. A rare variant burden analysis using next-generation sequencing data from 637 BAV/TAA patients was performed for these two candidate genes. This revealed a suggestive genetic role for TBX20 in BAV/TAA aetiology, further reinforced by segregation of a rare TBX20 variant with the phenotype within a BAV/TAA family. To conclude, our results do not confirm a significant contribution for deleterious CNVs in BAV/TAA as only one potentially pathogenic CNV (1.05%) was identified. We cannot exclude the possibility that BAV/TAA is occasionally attributed to causal CNVs though, or that certain CNVs act as genetic risk factors by creating a sensitised background for BAV/TAA. Finally, accumulative evidence for TBX20 involvement in BAV/TAA aetiology underlines the importance of this transcription factor in cardiovascular disease.
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http://dx.doi.org/10.1038/s41431-019-0364-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777542PMC
July 2019

Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy.

Eur J Hum Genet 2019 07 22;27(7):1044-1053. Epub 2019 Feb 22.

Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Intriguingly, patients with craniosynostosis have also been reported to be explained molecularly by similar loss-of-function SMAD6 variants. While significantly reduced penetrance of craniosynostosis has been reported for the SMAD6 variants as such, near-complete penetrance is reached upon co-occurrence with a common BMP2 SNP risk allele. Here, we report on the results of a SMAD6-variant analysis in 473 unrelated non-syndromic TAA patients, of which the SMAD6-positive individuals were also studied for the presence of the BMP2 risk allele. Although only 14% of the TAA patients also presented BAV, all novel likely pathogenic SMAD6 variants (N = 7) were identified in BAV/TAA individuals, further establishing the role of SMAD6 variants to the aetiology of BAV/TAA and revealing limited contribution to TAA development in patients with a tricuspid aortic valve. Familial segregation studies confirmed reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity. None of our six BMP2+/SMAD6+ patients presented with craniosynostosis. Hence, the proposed digenic model for craniosynostosis was not supported in the presented BAV/TAA cohort, suggesting that additional factors are at play. Finally, our data provide improved insights into the clinical spectrum of SMAD6-related BAV/TAA and has important implications for molecular diagnostics.
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http://dx.doi.org/10.1038/s41431-019-0363-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777625PMC
July 2019