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Background and aim: Noonan syndrome (NS) is associated with different types of heart defects of which a supravalvular pulmonary stenosis ((SV)PS) is the most frequent. Possible treatment options are percutaneous balloon pulmonary valvuloplasty (BVP) or surgical intervention. Anatomical location of the PS may help predict BVP failure. We aimed to identify factors predicting treatment outcome and reintervention rate of BVP in PS, in children with NS. Methods: Medical records of children with a diagnosis of NS and in follow-up at Antwerp- and Ghent University Hospitals from 2000 to 2022 were retrospectively reviewed. Results: 32 children were identified with a SVPS, either isolated or in combination with other heart defects. 69% of children with PS had SVPS. The prevalence of PS and SVPS was similar for all genes. An isolated SVPS was identified as a risk factor for intervention. An intervention was necessary in 17/32 patients (53%). All but 2 children with pulmonary valve stenosis had SVPS. Only 2 of 17 patients had primary surgical repair. The remaining 15 (13 with SVPS) underwent BVP, of which 10 (67%) needed a second intervention, but all of them ultimately needed surgical repair. The global success rate of BVP was (31,1%). Conclusion: SVPS is the most frequent heart defect in children with NS. The prevalence of SVPS was similar for all genes. Isolated SVPS is a risk factor for intervention. The success rate of BVP in patients with NS is low. BVP might still be useful in selected cases and might be considered to clarify the anatomical location of PS.

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent–offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with ‘damaging’ in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.

Arrhythmia; Heritable thoracic aortic disease Arritmia; Enfermedad hereditaria de la aorta torácica Arrítmia; Malaltia hereditària de l'aorta toràcica Background Heritable thoracic aortic diseases (HTAD), typically entailing aortic complications, can be caused by pathogenic variants or likely pathogenic variants (PV/LPVs) in several genes, including fibrillin1 (FBN1), Actin Alpha2 (ACTA2) and genes encoding components of the transforming growth factor (TGF)-β signaling pathway. In addition to aortic complications, non-aortic cardiac disease such as impaired myocardial function and/or arrhythmia have been increasingly reported, mainly in Marfan syndrome with underlying FBN1 PV/LPVs and are acknowledged as additional causes of morbidity and mortality. The prevalence of these manifestations in the various HTAD entities is largely unknown. Methods This international multicentre retrospective study collected data on patients with HTAD presenting non-aortic cardiac disease. A total of 9 centers from 7 different countries participated. Patients 12 years or older carrying a PV/LPV in one of the following genes: FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3 and ACTA2 were screened. Non-aortic cardiac disease included impaired myocardial function and/or arrhythmia. Impaired myocardial function was defined as (a)symptomatic reduced ejection fraction (EF

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

Resumen En los ultimos anos, la genetica ha adquirido merecidamente un lugar importante en casi todas las disciplinas medicas, y este tambien es el caso en el campo de las cardiopatias congenitas. Esto no solo ha llevado a una mejor comprension de la fisiopatologia de los defectos cardiacos congenitos, sino que tambien conlleva un impacto positivo en el tratamiento del paciente. La integracion de la genetica clinica en centros acreditados para el abordaje de las cardiopatias congenitas es sin duda una recomendacion clara. Los cardiologos pediatricos y de adultos tienen un papel crucial en el proceso de evaluacion genetica de los pacientes y sus familias, por lo que deben conocer las senales de alerta que justifiquen un estudio genetico mas o menos elaborado, asi como el asesoramiento y la realizacion de otras pruebas. Para la correcta interpretacion de los resultados de las pruebas geneticas, es esencial disponer de algunos conocimientos basicos. En este documento de revision se proporciona una vision general practica de lo que implica la evaluacion genetica, que tipo de pruebas geneticas son posibles hoy y como se aplican al paciente individual en la practica clinica.

Background Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS) and related heritable thoracic aortic diseases (HTAD) are well-known for their aortic complications. Myocardial dysfunction and arrhythmia are less known in this setting but have been increasingly reported as additional causes of morbidity and mortality. Related to the rarity of the disorders, data on the prevalence of these features and clinical characteristics of the patients are difficult to obtain, calling for a multicentre initiative. Purpose To study the prevalence of myocardial dysfunction and arrhythmia in patients with HTAD and describe their clinical and genetic profile. Methods Nine centres from seven countries participated in this multicentre retrospective study. Medical records of patients 12 years or older carrying a (likely) pathogenic variant in the FBN1 gene, LDS genes (TGFBR1, TGFBR2, TGFB2, TGFB3 and SMAD3) or ACTA2 gene were screened. Patients presenting myocardial dysfunction and/or arrhythmia were identified, and clinical and genetic data were collected. Myocardial dysfunction included (a)symptomatic reduced ejection fraction (EF Results In total, 3219 patients with HTAD were screened: 2761 with a variant in FBN1, 385 with a variant in one of the LDS genes (TGFBR1, TGFBR2, TGFB2, TGFB3 and SMAD3) and 73 carrying a variant in ACTA2. Myocardial dysfunction and arrhythmia were not reported in patients carrying an ACTA2 variant. Myocardial dysfunction was observed in patients with a variant in FBN1 and the LDS genes, without significant differences in prevalence (2.3% vs. 1.8%, p=0.563). Patients with a variant in the LDS genes presenting myocardial dysfunction were younger than patients carrying a variant in FBN1 (25±11 years vs. 39±17 years, p=0.034). The prevalence of VT/VF/SCD was similar in patients with a variant in one of the LDS genes compared to those with a variant in FBN1 (1.6% vs. 0.8%, p=0.132) and there was no difference in age at time of event (26±13 years vs. 33±14 years, p=0.289). Among patients with a variant in the LDS genes, the prevalence of VT/VF/SCD was highest in patients carrying a variant in the TGFBR2 gene and was significantly higher compared to patients with a variant in FBN1 (3.4% vs. 0.8%, p=0.017). In contrast, AF/AFL was significantly more often reported in patients with a variant in FBN1 compared to those with a variant in one of the LDS genes (1.7% vs. 0.3%, p=0.033). Conclusions Myocardial dysfunction and arrhythmia are rare features in patients with HTAD. They occur predominantly in patients with a variant in FBN1 and LDS genes, but were not reported in patients carrying a variant in the ACTA2 gene. Further analysis to identify other contributing factors is necessary. Funding Acknowledgement Type of funding sources: None. Figure 1

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 Fibrillin-1 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.

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 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.

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.

BackgroundPathogenic variants inSMAD3cause 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 withSMAD3variants.MethodsAortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 uniqueSMAD3variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.ResultsAortic 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 withSMAD3MH2 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.ConclusionsSMAD3pathogenic 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 underlyingSMAD3variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated withSMAD3variants support gene-specific management of this disorder.

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 (p1/2VO2: r = -0.517; p1minVO2: r = -0.636, p1minVCO2: r = -0.373, p = 0.012) and TAPSE (T1/2VO2: r = -0.505; p1minVO2: r = -0.566, p1/2VCO2: r = -0.466; p = 0.001; Rec1minVCO2: r = -0.507, p 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.

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype- and phenotype-oriented literature overview of all (n = 85) reported patients with ZNF469 (n = 53) and PRDM5 (n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition., SCOPUS: ar.j, info:eu-repo/semantics/published

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.

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.

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.

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.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.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.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.

Introduction: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features. Areas covered: 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. Expert commentary: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome.

Background: Pathogenic variants in TGFBR1, TGFBR2 and SMAD3 genes cause Loeys-Dietz syndrome, and pathogenic variants in FBN1 cause Marfan syndrome. Despite their similar phenotypes, both syndromes may have different cardiovascular outcomes. Methods: 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 &plusmn, 18 years. Twenty-six individuals had pathogenic variants in TGFBR1, 40 in TGFBR2, and 17 in SMAD3. For case-matched comparison we used 83 age and sex-frequency matched individuals with Marfan syndrome. Results: In Loeys-Dietz compared to Marfan syndrome, a patent ductus arteriosus (p = 0.014) was more prevalent, the craniofacial score was higher (p &lt, 0.001), the systemic score lower (p &lt, 0.001), and mitral valve prolapse less frequent (p = 0.003). Mean survival for Loeys-Dietz and Marfan syndrome was similar (75 &plusmn, 3 versus 73 &plusmn, 2 years, p = 0.811). Cardiovascular outcome was comparable between Loeys-Dietz and Marfan syndrome, including mean freedom from proximal aortic surgery (53 &plusmn, 4 versus 48 &plusmn, 3 years, p = 0.589), distal aortic repair (72 &plusmn, 3 versus 67 &plusmn, p = 0.777), mitral valve surgery (75 &plusmn, 4 versus 65 &plusmn, p = 0.108), and reintervention (20 &plusmn, 3 versus 14 &plusmn, p = 0.112). In Loeys-Dietz syndrome, lower age at initial presentation predicted proximal aortic surgery (HR = 0.748, p &lt, 0.001), where receiver operating characteristic analysis identified &le, 33.5 years with increased risk. In addition, increased aortic sinus diameters (HR = 6.502, p = 0.001), and higher systemic score points at least marginally (HR = 1.175, p = 0.065) related to proximal aortic surgery in Loeys-Dietz syndrome. Conclusions: Cardiovascular outcome of Loeys-Dietz syndrome was comparable to Marfan syndrome, but the severity of systemic manifestations was a predictor of proximal aortic surgery.

In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.

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 P < .001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P < .001). In contrast, the incidence of endocarditis (P = .292), heart failure (P = .644), and mitral valve surgery (P = .140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P = .013), moderate MVR (P = .019) and flail MV leaflet (P = .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. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background:The introduction of next-generation sequencing techniques has substantially increased the identification of new genetic variants and hence the necessity of accurate variant interpretatio...

See Article by Takeda, Inuzuka, and Maemura et al Since the middle of the past century, identification of the causal gene for monogenic disorders has undoubtedly led to improvement in diagnostics and knowledge of the pathophysiological mechanisms underlying these disorders. Yet an explanation for the often extensive variability in the clinical expression of diseases caused by variants in the same gene often remains elusive, and this is no less the case for Marfan syndrome (MFS). MFS is an autosomal dominant inherited connective tissue disorder, caused by pathogenic variants in the fibrillin 1 gene ( FBN1 ). This gene encodes the extracellular matrix protein, fibrillin1, which plays an essential structural role in the assembly of the microfibrils, as well as a functional role in the regulation of growth factors, such as transforming growth factor β and bone morphogenetic protein.1 MFS is a pleiotropic disease affecting predominantly the ocular, skeletal, and cardiovascular systems. Survival of patients with MFS is mainly determined by the degree of cardiovascular involvement. Progressive enlargement of the aortic root at the level of the sinuses of Valsalva in particular accounts for excess mortality because it may lead to life-threatening aortic dissection or rupture. Whereas the prognosis for people with MFS was initially bleak, mainly because of aortic complications, this has improved significantly for the past decades.2 This positive trend is not only because of optimization of medical and surgical treatment but also related to increased awareness and better diagnostics. Other cardiovascular features, present in a variable amount of patients, include mitral valve prolapse and myocardial dysfunction.3,4 To date, treatment of cardiovascular manifestations in patients with MFS is fairly uniform, with guidelines for medical treatment and (prophylactic) surgery based on simple parameters, such as age, body surface, and aortic diameters. Nevertheless, we know that not everyone …

PurposeWe 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.MethodsWe 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.ResultsStenoses, 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.ConclusionOur 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.GENETICS in MEDICINE advance online publication, 11 January 2018; doi:10.1038/gim.2017.253. ispartof: Genetics in Medicine vol:20 issue:10 pages:1236-1245 ispartof: location:United States status: published

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.

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.

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.To allow a more uniform interpretation of variants in theAgreement 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.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.

Women with genetic aortic disease, such as Marfan syndrome, are at increased risk of pregnancy complications, in particular those with aortic dissection [(1)][1]. Aneurysms-osteoarthritis syndrome (AOS) is an autosomal-dominant syndrome caused by SMAD3 mutations, and is characterized by arterial

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.

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.

[This corrects the article DOI: 10.1371/journal.pone.0181166.].

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.

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. Currently, additional in vitro assays using different hormones (estriol, dihydrotestosterone, progesterone, and oxytocin) are ongoing. 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. Additional in vitro experiments are ongoing.

Background Heritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported. Methods We performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative. Results A mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS. Conclusion NGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0221-6) contains supplementary material, which is available to authorized users.