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Purpose: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies. Methods: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire. Results: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of

Contains fulltext : 291759.pdf (Publisher’s version ) (Open Access) PURPOSE OF REVIEW: Structural genomic variants have emerged as a relevant cause for several disorders, including intellectual disability, neuropsychiatric disorders, cancer and congenital heart disease. In this review, we will discuss the current knowledge about the involvement of structural genomic variants and, in particular, copy number variants in the development of thoracic aortic and aortic valve disease. RECENT FINDINGS: There is a growing interest in the identification of structural variants in aortopathy. Copy number variants identified in thoracic aortic aneurysms and dissections, bicuspid aortic valve related aortopathy, Williams-Beuren syndrome and Turner syndrome are discussed in detail. Most recently, the first inversion disrupting FBN1 has been reported as a cause for Marfan syndrome. SUMMARY: During the past 15 years, the knowledge on the role of copy number variants as a cause for aortopathy has grown significantly, which is partially due to the development of novel technologies including next-generation sequencing. Although copy number variants are now often investigated on a routine basis in diagnostic laboratories, more complex structural variants such as inversions, which require the use of whole genome sequencing, are still relatively new to the field of thoracic aortic and aortic valve disease.

Marfan syndrome (MFS) is a connective tissue disorder with pleiotropic manifestations in the ocular, skeletal and cardiovascular system. Ruptured aortic aneurysms in MFS patients are associated with high mortality rates. MFS is typically caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Here, we report a generated induced pluripotent cell (iPSC) line of a MFS patient with a FBN1 c.5372G > A (p.Cys1791Tyr) variant. For that, skin fibroblasts of a MFS patient carrying a FBN1 c.5372G > A (p.Cys1791Tyr) variant were successfully reprogrammed into iPSCs using the CytoTuneTM-iPS 2.0 Sendai Kit (Invitrogen). The iPSCs showed a normal karyotype, expressed pluripotency markers, were able to differentiate into three germ layers and carried the original genotype.

The class I small leucine-rich proteoglycan biglycan is a crucial structural extracellular matrix component that interacts with a wide range of extracellular matrix molecules. In addition, biglycan is involved in sequestering growth factors such as transforming growth factor-β and bone morphogenetic proteins and thereby regulating pathway activity. Biglycan consists of a 42-kDa core protein linked to two glycosaminoglycan side chains and both are involved in protein interactions. Biglycan is encoded by the BGN gene located on the X-chromosome and is expressed in various tissues, including vascular tissue, skin, brain, kidney, lung, the immune system, and the musculoskeletal system. Although an increasing amount of data on the biological function of biglycan in the vasculature has been produced, its role in thoracic aortic aneurysms is still not fully elucidated. This review focuses on the role of biglycan in the healthy thoracic aorta and the development of thoracic aortic aneurysm and dissections in both mice and humans.

Different pathogenic variants in the fibrillin‐1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints and hypermuscularity. Similarly, pathogenic variants in the fibrillin‐2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2‐related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2‐related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the “tall” and “short” fibrillinopathies. The future parallel functional study of both FBN1/2‐related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.

PURPOSE In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. METHODS Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. RESULTS We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. CONCLUSION Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.

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

BACKGROUND: The importance of genetic testing for cardiomyopathies has increased in the last decade. However, in heart transplant patients with former cardiomyopathy, genetic testing in retrospect is not routinely performed. We hypothesize that the yield of genetic testing in this population is considerable, and will have a major impact for both patients and relatives. METHODS: Patients that underwent heart transplantation (HTx) between 1995 and 2020 and were still in follow-up, were offered genetic testing if the primary etiology was non-ischemic cardiomyopathy. Next generation sequencing (NGS) of known cardiomyopathy genes was performed and variants were classified as variant of unknown significance (class 3), likely pathogenic (class 4) or pathogenic (class 5) variant. RESULTS: Of the 99 HTx patients in active follow-up, only 6 patients had a genetic diagnosis at the time of HTx. In this study, 31 selected patients with prior non-ischemic cardiomyopathy underwent genetic testing post HTx. 23/31 patients (74.2%) carried a variant that was classified as class 3 or higher. In 12/31 patients a class 4/5 variant (38.7%) was identified, and in 11/31 patients (35.5%) a class 3 variant. Class 5 Variants in TTN were the most prevalent (7/31), followed by class 5 variants in MYBPC3 (2/31). A positive family history was present in 21/31 (67.7%) and a second precipitating factor (e.g., alcohol abuse, pregnancy) was present in 17/31 patients (54.8%). Diagnostic yield of genetic testing was similar between patients with or without familial history and/or second hit. Through cascade screening 48 family members were screened for presence of a class 4/5 variant, of whom 19 (39.6%) were genotype positive, of whom 10 (52.6%) showed a cardiac phenotype. Appropriate follow-up was offered. CONCLUSIONS: Genetic testing for cardiomyopathy genes established a molecular diagnosis in 38.7% of patients post HTx. These results highlight the importance of genetic testing in this population as it is still often overlooked in patients that already underwent HTx in the past. Genetic testing is highly recommended, independent of family history or second precipitating factors, as it might identify relatives at risk. (C) 2022 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.

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Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%)

The extracellular matrix (ECM) is a complex entity with structural proteins (such as fibrillins, collagen, elastin), ground substance (proteoglycans), modifying enzymes (ADAMTS, PLOD, lysyloxidases (LOX)) and cytokines that regulate morphogenesis, growth, homeostasis and repair (transforming growth factor-beta [TGF-beta], bone morphogenic protein [BMP]). Over the last decade, the intimate relationship between structural proteins and these growth factors has emerged. The study of the extracellular matrix in human conditions and relevant mouse models is gradually unmasking the key role of these structural molecules in the regulation of the bio-availability of these growth factors. Major progress has been made in the study of the cardiovascular system (1) and the first clues in the skeletal system have emerged. (2) In this review, we will discuss the clinical, molecular, and pathogenic aspects of Marfan syndrome, Loeys-Dietz syndrome and related disorders with emphasis on the role of fibrillins and TGF-beta.

Background: Loeys-Dietz syndrome is a recently recognized multisystemic disorder caused by mutations in the genes encoding the transforming growth factor-beta receptor. It is characterized by aggressive aneurysm formation and vascular tortuosity. We report the musculoskeletal demographic, clinical, and imaging findings of this syndrome to aid in its diagnosis and treatment. Methods: We retrospectively analyzed the demographic, clinical, and imaging data of sixty-five patients with Loeys-Dietz syndrome seen at one institution from May 2007 through December 2008. Results: The patients had a mean age of twenty-one years, and thirty-six of the sixty-five patients were less than eighteen years old. Previous diagnoses for these patients included Marfan syndrome (sixteen patients) and Ehlers-Danlos syndrome (two patients). Spinal and foot abnormalities were the most clinically important skeletal findings. Eleven patients had talipes equinovarus, and nineteen patients had cervical anomalies and instability. Thirty patients had scoliosis (mean Cobb angle [and standard deviation], 30° ± 18°). Two patients had spondylolisthesis, and twenty-two of thirty-three who had computed tomography scans had dural ectasia. Thirty-five patients had pectus excavatum, and eight had pectus carinatum. Combined thumb and wrist signs were present in approximately one-fourth of the patients. Acetabular protrusion was present in approximately one-third of the patients and was usually mild. Fourteen patients had previous orthopaedic procedures, including scoliosis surgery, cervical stabilization, clubfoot correction, and hip arthroplasty. Features of Loeys-Dietz syndrome that are important clues to aid in making this diagnosis include bifid broad uvulas, hypertelorism, substantial joint laxity, and translucent skin. Conclusions: Patients with Loeys-Dietz syndrome commonly present to the orthopaedic surgeon with cervical malformations, spinal and foot deformities, and findings in the craniofacial and cutaneous systems. Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Purpose We examined the prevalence of known facial features of Marfan syndrome (MFS)—dolicocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures—and the diagnostic utility (sensitivity, specificity, accuracy, predictive values, and likelihood ratios) of using them for screening and diagnosis. Methods Frontal and lateral photographs of 76 subjects with MFS (average age 18.3 years) and of 76 age- and gender-matched controls were obtained, randomized, and compiled into an online survey. Three physicians experienced with MFS rated each photograph for the presence of each feature and indicated whether each photograph triggered a suspicion for MFS. Eight non-expert orthopaedic surgeons reviewed a subset of those photographs and indicated if each triggered a suspicion for MFS. Half of the non-experts then received a brief diagnosis instructional sheet, and all non-experts were retested. The results were compared using Chi-square tests and t-tests with a significance level of P < 0.05. Results Using facial features alone, the accuracy of experienced physicians in identifying individuals with MFS was 73%. Facial features had a 54% sensitivity, a 91% specificity, an 86% positive predictive value (PPV), a 67% negative predictive value (NPV), a 6.9% positive likelihood ratio (PLR), and a 50% negative likelihood ratio (NLR) for MFS. There was no significant difference in the diagnostic accuracy between non-experts receiving and not receiving instructions. Conclusions Facial features are more specific than sensitive for MFS. Therefore, the recognition of facial features of MFS can be used as an initial screening tool, but facial features do not have a high sensitivity for MFS.