Publications by authors named "Laura Muiño-Mosquera"

31 Publications

A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome.

Genes (Basel) 2021 07 8;12(7). Epub 2021 Jul 8.

Center for Medical Genetics, Ghent University Hospital, Belgium and Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.
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http://dx.doi.org/10.3390/genes12071048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304049PMC
July 2021

Cardiomyopathy in Genetic Aortic Diseases.

Front Pediatr 2021 15;9:682390. Epub 2021 Jul 15.

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

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.
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http://dx.doi.org/10.3389/fped.2021.682390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319542PMC
July 2021

Association of Mitral Annular Disjunction With Cardiovascular Outcomes Among Patients With Marfan Syndrome.

JAMA Cardiol 2021 Oct;6(10):1177-1186

Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Importance: Mitral annular disjunction (MAD) has received particular interest in patients with mitral valve prolapse, ventricular tachycardia, and sudden cardiac death. The clinical significance of MAD for patients with Marfan syndrome (MFS) remains largely unexplored.

Objective: To define the prevalence of MAD and examine its association with cardiovascular outcomes and arrhythmia among patients with MFS.

Design, Setting, And Participants: This retrospective, single-center cohort study included 142 patients with a diagnosis of MFS based on the revised Ghent criteria and a confirmed (likely) pathogenic variant in the FBN1 gene who underwent regular follow-up between January 1, 2004, and December 31, 2019.

Main Outcomes And Measures: The presence of MAD was assessed by echocardiography, and the extent of MAD was categorized in tertiles. Patients also underwent resting electrocardiography and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (defined as sustained ventricular tachycardia or sudden cardiac death), and mitral valve surgery.

Results: A total of 142 patients (72 female patients [51%]; median age at first examination, 25 years [range, 2-64 years]) were evaluated. Forty-eight patients (34%) had MAD. Patients with MAD had larger aortic root z scores than patients without MAD (4.1 [interquartile range, 2.8-5.7] vs 3.0 [interquartile range, 1.8-4.0]; P < .001) and more often had mitral valve prolapse (34 of 48 [71%] vs 14 of 94 [15%]; P < .001), ventricular ectopy (14 of 33 [42%] vs 15 of 70 [21%]; P = .03), and nonsustained ventricular tachycardia (13 of 33 [39%] vs 12 of 70 [17%]; P = .01). During follow-up, aortic events occurred at similar rates among patients with vs without MAD (15 of 43 [35%] vs 21 of 84 [25%]; P = .24), but patients in the upper MAD tertile (>10 mm) showed a higher occurrence of aortic events compared with patients with MAD of 10 mm or smaller (9 of 15 [60%] vs 6 of 28 [21%]; P = .01). Patients with arrhythmic events (n = 5) and patients requiring mitral valve surgery (n = 7) were observed exclusively in the group displaying MAD.

Conclusions And Relevance: This study suggests that MAD among patients with MFS is associated with the occurrence of arrhythmic events, a higher need for mitral valve intervention, and, among patients with extensive MAD, more aortic events. Cardiac imaging for patients with MFS should consider the assessment of MAD as a potential marker for adverse outcomes.
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http://dx.doi.org/10.1001/jamacardio.2021.2312DOI Listing
October 2021

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.

Nat Commun 2021 05 11;12(1):2628. Epub 2021 May 11.

Gene regulation in cardiovascular remodeling and inflammation group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
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http://dx.doi.org/10.1038/s41467-021-22933-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113458PMC
May 2021

Analysis of the recovery phase after maximal exercise in children with repaired tetralogy of Fallot and the relationship with ventricular function.

PLoS One 2020 18;15(12):e0244312. Epub 2020 Dec 18.

Department of Pediatric Cardiology, Ghent University Hospital, Ghent, Belgium.

Background: Few studies demonstrate delayed recovery after exercise in children and adults with heart disease. We assess the recovery patterns of gas exchange parameters and heart rate (HR) in children with repaired Tetralogy of Fallot (rToF) compared to healthy peers and investigate the correlation with ventricular function and QRS duration.

Methods: 45 children after rToF and 45 controls performed a maximal incremental cardiopulmonary exercise test. In the subsequent recovery period, patterns of VO2, VCO2 and HR were analysed. Half-life time (T1/2) of the exponential decay and drop per minute (Recmin) were compared between groups. In the rToF group, correlations were examined between the recovery parameters and QRS-duration and ventricular function, described by fractional shortening (FS) and tricuspid annular plane systolic excursion (TAPSE) measured at baseline prior to exercise.

Results: Recovery of VO2 and VCO2 was delayed in rToF patients, half-life time values were higher compared to controls (T1/2VO2 52.51 ±11.29 s vs. 44.31 ± 10.47 s; p = 0.001 and T1/2VCO2 68.28 ± 13.84 s vs. 59.41 ± 12.06 s; p = 0.002) and percentage drop from maximal value was slower at each minute of recovery (p<0.05). Correlations were found with FS (T1/2VO2: r = -0.517; p<0.001; Rec1minVO2: r = -0.636, p<0.001; Rec1minVCO2: r = -0.373, p = 0.012) and TAPSE (T1/2VO2: r = -0.505; p<0.001; Rec1minVO2: r = -0.566, p<0.001; T1/2VCO2: r = -0.466; p = 0.001; Rec1minVCO2: r = -0.507, p<0.001), not with QRS-duration. No difference was found in HR recovery between patients and controls.

Conclusions: Children after rToF show a delayed gas exchange recovery after exercise. This delay correlates to ventricular function, demonstrating its importance in recovery after physical activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748266PMC
March 2021

Myocardial disease and ventricular arrhythmia in Marfan syndrome: a prospective study.

Orphanet J Rare Dis 2020 10 23;15(1):300. Epub 2020 Oct 23.

Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Background: Aortic root dilatation and-dissection and mitral valve prolapse are established cardiovascular manifestations in Marfan syndrome (MFS). Heart failure and arrhythmic sudden cardiac death have emerged as additional causes of morbidity and mortality.

Methods: To characterize myocardial dysfunction and arrhythmia in MFS we conducted a prospective longitudinal case-control study including 86 patients with MFS (55.8% women, mean age 36.3 yr-range 13-70 yr-) and 40 age-and sex-matched healthy controls. Cardiac ultrasound, resting and ambulatory ECG (AECG) and NT-proBNP measurements were performed in all subjects at baseline. Additionally, patients with MFS underwent 2 extra evaluations during 30 ± 7 months follow-up. To study primary versus secondary myocardial involvement, patients with MFS were divided in 2 groups: without previous surgery and normal/mild valvular function (MFS-1; N = 55) and with previous surgery or valvular dysfunction (MFS-2; N = 31).

Results: Compared to controls, patients in MFS-1 showed mild myocardial disease reflected in a larger left ventricular end-diastolic diameter (LVEDD), lower TAPSE and higher amount of (supra) ventricular extrasystoles [(S)VES]. Patients in MFS-2 were more severely affected. Seven patients (five in MFS-2) presented decreased LV ejection fraction. Twenty patients (twelve in MFS-2) had non-sustained ventricular tachycardia (NSVT) in at least one AECG. Larger LVEDD and higher amount of VES were independently associated with NSVT.

Conclusion: Our study shows mild but significant myocardial involvement in patients with MFS. Patients with previous surgery or valvular dysfunction are more severely affected. Evaluation of myocardial function with echocardiography and AECG should be considered in all patients with MFS, especially in those with valvular disease and a history of cardiac surgery.
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http://dx.doi.org/10.1186/s13023-020-01581-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585308PMC
October 2020

Myocardial Function, Heart Failure and Arrhythmia in Marfan Syndrome: A Systematic Literature Review.

Diagnostics (Basel) 2020 Sep 25;10(10). Epub 2020 Sep 25.

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

Marfan syndrome (MFS) is a heritable systemic connective tissue disease with important cardiovascular involvement, including aortic root dilatation and mitral valve prolapse. Life expectancy in patients with MFS is mainly determined by cardiovascular complications, among which aortic dissection or rupture are most dreaded. In recent years, heart failure and ventricular arrhythmia have drawn attention as extra-aortic cardiovascular manifestations and as additional reported causes of death. Imaging studies have provided data supporting a primary myocardial impairment in the absence of valvular disease or cardiovascular surgery, while studies using ambulatory ECG have demonstrated an increased susceptibility to ventricular arrhythmia. In this paper, current literature was reviewed in order to provide insights in characteristics, pathophysiology and evolution of myocardial function, heart failure and ventricular arrhythmia in MFS.
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http://dx.doi.org/10.3390/diagnostics10100751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599866PMC
September 2020

A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations.

Genet Med 2021 01 29;23(1):94-102. Epub 2020 Sep 29.

Mindich Child Health and Development Institute, Icahn School of Medicine, New York, NY, USA.

Purpose: The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data.

Methods: This study uses exome sequencing and corresponding phenotypic data from Mount Sinai's BioMe (n = 32,344) and the United Kingdom Biobank (UKBB; n = 49,960). Variant curation identified pathogenic/likely pathogenic (P/LP) variants in RASopathy genes and FBN1.

Results: Twenty-one subjects harbored P/LP RASopathy variants; three (14%) were diagnosed, and another 46% had ≥1 classic Noonan syndrome (NS) feature. Major NS features (short stature [9.5% p = 7e-5] and heart anomalies [19%, p < 1e-5]) were less frequent than expected. Prevalence of hypothyroidism/autoimmune disorders was enriched compared with biobank populations (p = 0.007). For subjects with FBN1 P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. Five of 15 participants (33%) with echocardiographic data had aortic dilation, fewer than expected (p = 8e-6). Ectopia lentis affected only 15% (p < 1e-5).

Conclusions: Substantial fractions of individuals harboring P/LP variants with partial or full phenotypic matches to a RASopathy or MFS remain undiagnosed, some not meeting diagnostic criteria. Routine population genotyping would enable multidisciplinary care and avoid life-threatening events.
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http://dx.doi.org/10.1038/s41436-020-00973-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796917PMC
January 2021

Genetics in congenital heart disease. Are we ready for it?

Rev Esp Cardiol (Engl Ed) 2020 Jul 6. Epub 2020 Jul 6.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Division of Pediatric Cardiology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.

Genetics has rightly acquired an important place in almost all medical disciplines in recent years and this is certainly the case in the field of congenital cardiology. Not only has this led to greater insight into the pathophysiology of congenital heart defects but it also has a beneficial impact on patient management. Integration of clinical genetics in multidisciplinary centers of expertise for CHD is therefore a clear recommendation. Adult and pediatric cardiologists play a crucial role in the process of genetic evaluation of patients and families and should have be familiar with red flags for referral for further clinical genetic elaboration, counseling, and eventual testing. Some basic knowledge is also important for the correct interpretation of genetic testing results. In this review article, we provide a practical overview of what genetic evaluation entails, which type of genetic tests are possible today, and how this can be used in practice for the individual patient.
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http://dx.doi.org/10.1016/j.rec.2020.05.019DOI Listing
July 2020

Angiotensin-II receptor blockade in Marfan syndrome.

Lancet 2019 12 10;394(10216):2206-2207. Epub 2019 Dec 10.

Centre for Medical Genetics, Ghent University Hospital, Ghent 9000, Belgium; Department of Cardiology, Ghent University Hospital, Ghent 9000, Belgium.

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http://dx.doi.org/10.1016/S0140-6736(19)32536-XDOI Listing
December 2019

Features of Marfan syndrome not listed in the Ghent nosology - the dark side of the disease.

Expert Rev Cardiovasc Ther 2019 Dec;17(12):883-915

Center for Medical Genetics and Department of Cardiology, Ghent University Hospital, VASCERN HTAD European Reference Centre, Ghent, Belgium.

: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features.: The German Marfan Organization listed unusual symptoms and clinical experts reviewed the literature on clinical features of Marfan syndrome not listed in the Ghent nosology. Thereby we identified the following features: (1) bicuspid aortic valve, mitral valve prolapse, pulmonary valve prolapse, tricuspid valve prolapse, (2) heart failure and cardiomyopathy, (3) supraventricular arrhythmia, ventricular arrhythmia, and abnormal repolarization, (4) spontaneous coronary artery dissection, anomalous coronary arteries, and atherosclerotic coronary artery disease, tortuosity-, aneurysm-, and dissection of large and medium-sized arteries, (5) restrictive lung disease, parenchymal lung disease, and airway disorders, (6) obstructive- and central sleep apnea, (7) liver and kidney cysts, biliary tract disease, diaphragmatic hernia, and adiposity, (8) premature labor, and urinary incontinence, (9) myopathy, reduced bone mineral density, and craniofacial manifestations, (10) atrophic scars, (11) caries, and craniomandibular dysfunction, (12) headache from migraine and spontaneous cerebrospinal fluid leakage, (13) cognitive dysfunction, schizophrenia, depression, fatigue, and pain, (14) and activated fibrinolysis, thrombin, platelets, acquired von Willebrand disease, and platelet dysfunction.: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome.
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http://dx.doi.org/10.1080/14779072.2019.1704625DOI Listing
December 2019

Case-matched Comparison of Cardiovascular Outcome in Loeys-Dietz Syndrome versus Marfan Syndrome.

J Clin Med 2019 Nov 29;8(12). Epub 2019 Nov 29.

Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum München, Technical University München, 80636 Munich, Germany.

Pathogenic variants in , and genes cause Loeys-Dietz syndrome, and pathogenic variants in cause Marfan syndrome. Despite their similar phenotypes, both syndromes may have different cardiovascular outcomes. Three expert centers performed a case-matched comparison of cardiovascular outcomes. The Loeys-Dietz group comprised 43 men and 40 women with a mean age of 34 ± 18 years. Twenty-six individuals had pathogenic variants in , 40 in , and 17 in . For case-matched comparison we used 83 age and sex-frequency matched individuals with Marfan syndrome. In Loeys-Dietz compared to Marfan syndrome, a patent ductus arteriosus ( = 0.014) was more prevalent, the craniofacial score was higher ( < 0.001), the systemic score lower ( < 0.001), and mitral valve prolapse less frequent ( = 0.003). Mean survival for Loeys-Dietz and Marfan syndrome was similar (75 ± 3 versus 73 ± 2 years; = 0.811). Cardiovascular outcome was comparable between Loeys-Dietz and Marfan syndrome, including mean freedom from proximal aortic surgery (53 ± 4 versus 48 ± 3 years; = 0.589), distal aortic repair (72 ± 3 versus 67 ± 2 years; = 0.777), mitral valve surgery (75 ± 4 versus 65 ± 3 years; = 0.108), and reintervention (20 ± 3 versus 14 ± 2 years; = 0.112). In Loeys-Dietz syndrome, lower age at initial presentation predicted proximal aortic surgery (HR = 0.748; < 0.001), where receiver operating characteristic analysis identified ≤33.5 years with increased risk. In addition, increased aortic sinus diameters (HR = 6.502; = 0.001), and higher systemic score points at least marginally (HR = 1.175; = 0.065) related to proximal aortic surgery in Loeys-Dietz syndrome. Cardiovascular outcome of Loeys-Dietz syndrome was comparable to Marfan syndrome, but the severity of systemic manifestations was a predictor of proximal aortic surgery.
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http://dx.doi.org/10.3390/jcm8122079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947024PMC
November 2019

Sleep apnea and the impact on cardiovascular risk in patients with Marfan syndrome.

Mol Genet Genomic Med 2019 08 27;7(8):e805. Epub 2019 Jun 27.

Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Background: Marfan syndrome (MFS) is an inherited connective tissue disorder characterized by ectopia lentis, aortic root dilation and dissection and specific skeletal features. Obstructive sleep apnea (OSA) in MFS has been described earlier but the prevalence and its relation with the cardiovascular risk is still controversial. This study aimed to further investigate these aspects.

Methods: In this prospective longitudinal study, we performed an attended polysomnography in 40 MFS patients (60% women, 37 ± 12.8 years) and evaluated several cardiovascular parameters through echocardiography, resting electrocardiogram, 24 hr-Holter monitoring and serum NT-ProBNP measurements.

Results: We found that OSA was present in 42.5% of the patients and that higher body mass index was the most important factor associated with the presence of OSA. We observed that overweight was present in 27.5% of the patients in the whole cohort and in 55.6% if >40 years. Furthermore, when evaluating the impact of OSA on the cardiovascular system, we observed that patients with OSA tended to have higher systolic blood pressure, larger distal aortic diameters and a higher prevalence of ventricular arrhythmia. These differences were, however, not significant after adjusting for confounders.

Conclusions: Our study shows a high prevalence of OSA and a high prevalence of overweight in MFS patients. We found some trends between OSA and cardiovascular features but we could not establish a solid association. Our study, however might be underpowered, and a multicenter collaborative study could be very useful to answer some important open questions.
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http://dx.doi.org/10.1002/mgg3.805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687621PMC
August 2019

pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium.

J Med Genet 2019 04 19;56(4):252-260. Epub 2019 Jan 19.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, USA.

Background: Pathogenic variants in cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with variants.

Methods: Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.

Results: Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.

Conclusions: pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with variants support gene-specific management of this disorder.
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http://dx.doi.org/10.1136/jmedgenet-2018-105583DOI Listing
April 2019

Frequency of Ventricular Arrhythmias and Other Rhythm Abnormalities in Children and Young Adults With the Marfan Syndrome.

Am J Cardiol 2018 10 17;122(8):1429-1436. Epub 2018 Jul 17.

Departments of Cardiology and Pediatrics, Boston Children's Hospital, Boston, Massachusetts.

Patients with the Marfan syndrome (MFS) are at risk for sudden death. The contribution of arrhythmias is unclear. This study examines the prevalence of arrhythmias in children with the MFS and their relation to clinical and/or echocardiographic factors. Data from the Pediatric Heart Network randomized trial of atenolol versus losartan in MFS were analyzed (6 months to 25 years old, aortic root diameter z-score > 3.0, no previous aortic surgery and/or dissection). Baseline 24-hour ambulatory electrocardiographic monitoring was performed. Significant ventricular ectopy (VE) and supraventricular ectopy (SVE) were defined as ≥10 VE or SVE/hour, or the presence of high-grade ectopy. Three-year composite clinical outcome of death, aortic dissection, or aortic root replacement was analyzed. There were 274 analyzable monitors on unique patients from 11 centers. Twenty subjects (7%) had significant VE, 13 (5%) significant SVE; of these, 2 (1%) had both. None had sustained ventricular or supraventricular tachycardia. VE was independently associated with increasing number of major Ghent criteria (odds ratio [OR] = 2.13/each additional criterion, p = 0.03) and greater left ventricular end-diastolic dimension z-score (OR = 1.47/each 1 unit increase in z-score, p = 0.01). SVE was independently associated with greater aortic sinotubular junction diameter z-score (OR = 1.56/each 1 unit increase in z-score, p = 0.03). The composite clinical outcome (14 events) was not related to VE or SVE (p ≥ 0.3), but was independently related to heart rate variability (higher triangular index). In conclusion, in this cohort, VE and SVE were rare. VE was related to larger BSA-adjusted left ventricular size. Routine ambulatory electrocardiographic monitoring may be useful for risk stratification in select MFS patients.
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http://dx.doi.org/10.1016/j.amjcard.2018.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497148PMC
October 2018

Tailoring the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines for the Interpretation of Sequenced Variants in the Gene for Marfan Syndrome: Proposal for a Disease- and Gene-Specific Guideline.

Circ Genom Precis Med 2018 06;11(6):e002039

Center for Medical Genetics (L.M.-M., F.S., I.M., A.D.P., W.S., S.S., P.C., B.C., M.R., J.D.B.).

Background: The introduction of next-generation sequencing techniques has substantially increased the identification of new genetic variants and hence the necessity of accurate variant interpretation. In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology proposed new variant interpretation guidelines. Gene-specific characteristics were, however, not considered, sometimes leading to inconsistent variant interpretation.

Methods: To allow a more uniform interpretation of variants in the (fibrillin-1) gene, causing Marfan syndrome, we tailored these guidelines to this gene and disease. We adapted 15 of the 28 general criteria and classified 713 variants previously identified in our laboratory as causal mutation or variant of uncertain significance according to these adapted guidelines. We then compared the agreement between previous methods and the adapted American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria.

Results: Agreement between the methods was 86.4% (K-alpha, 0.6). Application of the tailored guidelines resulted in an increased number of variants of uncertain significance (14.5% to 24.2%). Of the 85 variants that were downscaled to likely benign or variant of uncertain significance, 59.7% were missense variants outside a well-established functional site. Available clinical- or segregation data, necessary to further classify these types of variants, were in many cases insufficient to aid the classification.

Conclusions: Our study shows that classification of variants remains challenging and may change over time. Currently, a higher level of evidence is necessary to classify a variant as pathogenic. Gene-specific guidelines may be useful to allow a more precise and uniform interpretation of the variants to accurately support clinical decision-making.
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http://dx.doi.org/10.1161/CIRCGEN.117.002039DOI Listing
June 2018

Arterial tortuosity syndrome: 40 new families and literature review.

Genet Med 2018 10 11;20(10):1236-1245. Epub 2018 Jan 11.

Pediatrics Department, Kuwait University, Kuwait City, Kuwait.

Purpose: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.

Methods: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.

Results: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.

Conclusion: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.
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http://dx.doi.org/10.1038/gim.2017.253DOI Listing
October 2018

Sex, pregnancy and aortic disease in Marfan syndrome.

PLoS One 2017 14;12(7):e0181166. Epub 2017 Jul 14.

Department of Molecular & Medical Genetics and Biochemistry & Molecular Biology, Shriners Hospital for Children, Portland, Oregon, United States of America.

Background: Sex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these observations are largely unknown.

Objectives: In an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17β-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts.

Results: Our small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non-pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17β-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells.

Conclusions: Pregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510874PMC
September 2017

Efficacy of losartan as add-on therapy to prevent aortic growth and ventricular dysfunction in patients with Marfan syndrome: a randomized, double-blind clinical trial.

Acta Cardiol 2017 Dec 28;72(6):616-624. Epub 2017 Jun 28.

a Department of Medical Genetics , University Hospital Ghent , Ghent , Belgium.

Background: Marfan syndrome (MFS) is a multisystemic hereditary connective tissue disease. Aortic root aneurysms and dissections are the most common and life-threatening cardiovascular disorders affecting these patients. Other cardiac manifestations include mitral valve prolapse, ventricular dysfunction and arrhythmias. Medical treatment of cardiovascular features is ultimately aimed at slowing down aortic root growth rate and preventing dissection. Losartan has been proposed as a new therapeutic tool for this purpose. To which extent losartan affects cardiac function has not been studied previously.

Methods: We designed a prospective, double-blind, randomized placebo-controlled trial to evaluate the effect of losartan added to beta-blocker therapy on aortic growth and ventricular function in patients with MFS. Secondary outcomes were aortic dissection, prophylactic aortic surgery and death.

Results: Twenty-two patients were enrolled in the trial. There was a mild and similar increase in the aortic root during the 3 years of follow-up in both groups (median 1 mm, IQR [-1-1.5] and 1 mm, IQR [-0.25-1] in the losartan and placebo group, respectively, p = 1). Diastolic and systolic ventricular function was normal at baseline in both groups and remained stable during the study. One patient in the placebo group presented a subclavian artery dissection during follow-up.

Conclusion: Losartan on top of beta-blocker therapy has no additional effect on aortic growth or on cardiac function in patients with MFS. Our results are underpowered but are in line with the result from other groups. In order to have a better insight on whether a group of patients could benefit more from losartan therapy, the outcome of an on-going meta-analysis should be awaited.
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http://dx.doi.org/10.1080/00015385.2017.1314134DOI Listing
December 2017

International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium).

Circ Cardiovasc Genet 2016 Dec 21;9(6):548-558. Epub 2016 Nov 21.

Background: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive.

Methods And Results: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2. Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies.

Conclusions: Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177493PMC
December 2016

PGM1 deficiency diagnosed during an endocrine work-up of low IGF-1 mediated growth failure.

Acta Clin Belg 2016 Dec 24;71(6):435-437. Epub 2016 May 24.

a Division of Paediatric Endocrinology , University Hospital Brussels , Brussels , Belgium.

Objective And Importance: Phosphoglucomutase 1 (PGM1) deficiency, first described as a glycogenosis (type XIV) is also a congenital disorder of glycosylation (CDG). We want to illustrate the wide clinical spectrum of PGM1 deficiency and in particular the associated disturbance in glucose metabolism and the endocrine dysfunction. Treatment with d-galactose is experimental.

Case Presentation: PGM1 deficiency was diagnosed in an 8-year-old boy, who was referred because of an unexplained complex syndrome, including recurrent hypoglycaemia and low IGF-1 mediated growth failure.

Conclusion: The timely diagnosis of this disorder is particularly important, because d-galactose treatment can improve the latter symptoms.
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http://dx.doi.org/10.1080/17843286.2016.1142043DOI Listing
December 2016

Megaconial muscular dystrophy caused by mitochondrial membrane homeostasis defect, new insights from skeletal and heart muscle analyses.

Mitochondrion 2016 Mar 23;27:32-8. Epub 2016 Feb 23.

Laboratories of Neurogenetics and Ultrastructural Neuropathology and Biobank, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; Neurogenetics Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, B-2610 Antwerpen, Belgium; Department of Neurology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium.

Megaconial congenital muscular dystrophy is a disease caused by pathogenic mutations in the gene encoding choline kinase beta (CHKB). Microscopically, the disease is hallmarked by the presence of enlarged mitochondria at the periphery of skeletal muscle fibres leaving the centre devoid of mitochondria. Clinical characteristics are delayed motor development, intellectual disability and dilated cardiomyopathy in half of reported cases. This study describes a patient presenting with the cardinal clinical features, in whom a homozygous nonsense mutation (c.248_249insT; p.Arg84Profs*209) was identified in CHKB and who was treated by heart transplantation. Microscopic evaluation of skeletal and heart muscles typically showed enlarged mitochondria. Spectrophotometric evaluation in both tissues revealed a mild decrease of all OXPHOS complexes. Using BN-PAGE analysis followed by activity staining subcomplexes of complex V were detected in both tissues, indicating incomplete complex V assembly. Mitochondrial DNA content was not depleted in analysed tissues. This is the first report describing the microscopic and biochemical abnormalities in the heart from an affected patient. A likely hypothesis is that the biochemical findings are caused by an abnormal lipid profile in the inner mitochondrial membrane resulting from a defective choline kinase B activity.
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http://dx.doi.org/10.1016/j.mito.2016.02.001DOI Listing
March 2016

Mitral valve prolapse syndrome and MASS phenotype: Stability of aortic dilatation but progression of mitral valve prolapse.

Int J Cardiol Heart Vasc 2016 Mar 21;10:39-46. Epub 2016 Jan 21.

Centre of Cardiology and Cardiovascular Surgery, University Medical Center Hamburg-Hospital Eppendorf, Hamburg, Germany.

Background: Mitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS.

Methods: This retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38 ± 17 years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42 ± 15 years with mean follow-up of 66 ± 49 months.

Results: At baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all  < .001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications ( < .001). In contrast, the incidence of endocarditis ( = .292), heart failure ( = .644), and mitral valve surgery ( = .140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic ( = .013), moderate MVR ( = .019) and flail MV leaflet ( = .017) as independent predictors of mitral valve surgery.

Conclusions: The study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse.
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http://dx.doi.org/10.1016/j.ijcha.2016.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441352PMC
March 2016

Marfan Syndrome and Related Heritable Thoracic Aortic Aneurysms and Dissections.

Curr Pharm Des 2015 ;21(28):4061-75

Department of Cardiology and Medical Genetics, University Hospital Ghent, Belgium, De Pintelaan 185, 9000 Ghent, Belgium.

In this overview we aim to address a number of recent insights and developments regarding clinical aspects, etiology, and treatment of Heritable Thoracic Aortic Disease (H-TAD). We will focus on monogenetic disorders related to aortic aneurysms. H-TADs are rare but they provide a unique basis for the study of underlying pathogenetic pathways in the complex disease process of aneurysm formation. The understanding of pathomechanisms may help us to identify medical treatment targets to improve prognosis. Among the monogenetic aneurysm disorders, Marfan syndrome is considered as a paradigm entity and many insights are derived from the study of clinical, genetic and animal models for Marfan syndrome. We will therefore first provide a detailed overview of the various aspects of Marfan syndrome after which we will give an overview of related H-TAD entities.
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http://dx.doi.org/10.2174/1381612821666150826093152DOI Listing
July 2016

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans.

Pediatr Res 2015 Sep 4;78(3):256-63. Epub 2015 Jun 4.

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

Background: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding.

Methods: To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1(C1039G/+) mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction.

Results: Fbn1(C1039G/+) mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort.

Conclusion: In analogy with what is observed in the majority of MFS patients, the Fbn1(C1039G/+) mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS.
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http://dx.doi.org/10.1038/pr.2015.110DOI Listing
September 2015

Managing aortic aneurysms and dissections during pregnancy.

Expert Rev Cardiovasc Ther 2015 Jun 17;13(6):703-14. Epub 2015 May 17.

Department of Medical Genetics, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.

Cardiovascular diseases during pregnancy account for significant morbidity and mortality, with aortic aneurysms, complicated by aortic dissection or rupture, being high on the list of underlying causes in this category. Correct knowledge of the diagnosis, risks and treatment is mandatory to improve the outcome and save lives. In this article, the authors aim to provide an overview of the underlying causes and risk factors for aortic aneurysms and dissections during pregnancy, while presenting the ways of preventing and treating these conditions. Although an important focus lies on the proximal part of the aorta due to it bearing the greatest risk for complications and being more frequently implicated in aortic disease in younger subjects, many aspects on the etiology and underlying diseases also apply to the other parts of the vessel.
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http://dx.doi.org/10.1586/14779072.2015.1042862DOI Listing
June 2015
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