Familial Thoracic Aortic Aneurysms Research Articles

Cardiac genetic counseling services: Exploring downstream revenue in a pediatric medical center.

Genetic counseling is an important component of pediatric cardiac care. The financial costs and benefits of this care have yet to be defined in the literature. Downstream revenue (DSR) analysis can be used to assess the economic impact of genetic counselors (GCs) at their institution beyond the initial patient contact. Previous literature has reported DSR generated by oncology GCs, but there is no published DSR data from a cardiac GC setting. This study measured the DSR generated at a private hospital following a cardiac GC appointment. A chart review identified patients seen by a cardiac GC between 2018 and 2022. The study population included patients and their pediatric relatives who had not previously seen a cardiologist. Patients were included if they were affected with or at-risk for long QT syndrome, hypertrophic cardiomyopathy, dilated cardiomyopathy, or familial thoracic aortic aneurysm at the time of the GC visit. We recorded the frequency of common cardiac services and calculated the reimbursement for all cardiology services for 1 year following the initial GC appointment. The cohort included 121 participants from 61 families. Most individuals were at-risk for (n = 114, 94.3%) rather than affected by an inherited cardiac condition and presented for screening. The total DSR was $247,592.27, with an annual median of $1819.50 per patient (IQR $0, $3761.33). Revenue was similar among individuals who had undergone genetic testing and those who had not. Among participants, 72 (59.5%) had subsequent cardiology services. Most frequently, a patient who presented for subsequent care had an EKG, an echocardiogram, and a cardiology appointment. While the economic contributions of GC services do not speak to the broader value of GC involvement in patient care, they are important metrics for sustainability. This study outlines an approach to evaluating DSR and establishes a baseline understanding of DSR related to cardiac GC services.

A familial case of aortic dilatation with p.Tyr470Cys in TGFBR2 in which the phenotype included only vascular lesions.

Hereditary connective tissue diseases have different risks of aortic dissection depending on the causative gene. We report a family with no extravascular phenotype and a clinical diagnosis of familial thoracic aortic aneurysm and dissection, but genetic testing confirmed p.Tyr470Cys in TGFBR2, which is typically the responsible gene for Loeys-Dietz syndrome. Validation of the clinical diagnosis by genetic testing is warranted.

Multifocal Intracranial Stenosis and Thunderclap Headache in a Patient with Heterozygous MFAP5 Mutation for Familial Thoracic Aortic Aneurysm and Dissection

Recent investigations on familial thoracic aortic aneurysm and dissection (TAAD) identified several genetic variants. Meanwhile, intracranial vasculopathy in familial TAAD has been scarcely reported. We report a case of a young man with Marfanoid habitus and familial TAAD carrying MFAP5, c.472C>T variant. He presented with recurrent thunderclap headache and multifocal intracranial vasculopathy, which is predominantly suggestive of reversible cerebral vasoconstriction syndrome. While the role of MFAP5 in vasculopathy requires clarification, we propose its haploinsufficiency may contribute to both TAAD and intracranial stenosis, highlighting a potential risk of cerebrovascular disease in familial TAAD.

Stable thyroid cancer in a patient with thoracic aortic aneurysm and MYH11 variation.

We report the case of a male patient with papillary thyroid cancer, familial thoracic aortic aneurysm and dissection, and a variation in the MYH11 gene. Because of considerable tumor bulk in the neck that was not resectable, the patient underwent partial resection at age 14 years. Since then, the patient has received only suppressive thyroid hormone therapy. He is now 71 years old, which is 57 years after the initial resection. The patient received care at our institution from July 2009 to August 2019, during which we documented the stability of multiple calcified masses in the neck. Follow-up examinations at another institution from September 2019 to April 2023 also confirmed the stability of the masses. The underlying cause of this unusually long indolent course of the disease is unclear. Whether extensive tumor calcifications or the MYH11 sequence variation contributed to the disease course is also uncertain. Papillary thyroid cancer with neck metastases may, in some cases, be stable and remain asymptomatic for decades. If locoregional stability of papillary thyroid cancer is documented for many years, observation may be preferable to extensive neck surgery in selected cases. This is the first report of an MYH11 gene alteration and thoracic aortic aneurysm in a patient with papillary thyroid cancer with indolent neck metastases. Future studies of MYH11 gene alterations in thyroid carcinoma are needed.

Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is a multifactorial disorder. Familial TAA, which is more clinically aggressive, is associated with a high risk of lethal dissection or rupture. Genetic evaluation can provide TAA patients with personalized treatment and help in predicting risk to family members. The purpose of this investigation was to report a likely pathogenic variant in the EFEMP2 gene that may contribute to TAA in a family with a documented history of the condition. In the index patient, the causative genetic predisposition was identified using whole-exome sequencing. The potential likely pathogenic effect of the candidate variant was further analyzed through bioinformatics analysis, homology modeling, and molecular docking. The results revealed a likely pathogenic heterozygous variant, c.247C>T p.Arg83Cys, in exon 4 of the EFEMP2 gene (NM_016938), which was predicted to have disease-causing effects by MutationTaster, PROVEAN, SIFT, and CADD (phred score = 27.6). In this study, a likely pathogenic variant in the EFEMP2 gene was identified in an Iranian family with a dominant pattern of autosomal inheritance of TAA. This finding underscores the importance of conducting molecular genetic evaluations in families with nonsyndromic TAA and the significance of early detection of at-risk family members.

Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection.

Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca2+ concentration-multiple calcium channel expression and ADP-ribose synthesis-were attenuated in Myh11ΔK/ΔK aortas. We suggest that the impairment of the Ca2+ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.

Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases.

In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce. To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls. Patients with Loeys-Dietz syndrome (LDS, n = 12), Marfan syndrome (MFS, n = 11), and familial thoracic aortic aneurysm 6 (FTAA6, n = 9), i.e., actin alpha 2 (ACTA2) pathogenic variants, were recruited. Exome or genome sequencing was performed for genetic diagnosis. Several markers of inflammation and ECM remodeling were measured in plasma by enzyme immunoassays. Flow cytometry of T-cell subpopulations was performed on a subgroup of patients. For comparison, blood samples were drawn from 14 healthy controls. (i) All groups of HTAD patients had increased levels matrix metalloproteinase-9 (MMP-9) as compared with healthy controls, also in adjusted analyses, reflecting altered ECM remodeling. (ii) LDS patients had increased levels of pentraxin 3 (PTX3), reflecting systemic inflammation. (iii) LDS patients have increased levels of soluble CD25, a marker of T-cell activation. Our data suggest that upregulated MMP-9, a matrix degrading enzyme, is a common feature of several subgroups of HTAD. In addition, LDS patients have increased levels of PTX3 reflecting systemic and in particular vascular inflammation.

Sinus of Valsalva Aneurysm in Females.

Sinus of Valsalva aneurysm (SVA) is a rare cardiovascular disease with male predominance. Recently, an association with aortic aneurysm and SVA has been revealed in periventricular nodular heterotopia patients with loss-of-function Filamin A (FLNA) mutations, which were located on chromosome X and almost exclusively affect females.Among patients hospitalized for aortic surgery with aortic root diameter over 4.0 cm, next-generation sequencing was performed to investigate 30 candidate genes related to inherited aortic aneurysm syndromes and familial thoracic aortic aneurysm and dissection. The present report reviewed an electronic case database and identified two female cases of unruptured SVA with heterozygous FLNA truncating mutations.Case 1 displaying a rare SVA phenotype involving left and noncoronary sinus harbored a nonsense variant p.Tyr1720Ter/c.5160C > G. Case 2 displayed right and noncoronary SVA with predominantly enlarged right coronary sinus, posterior mitral valve prolapse, and harbored a frameshift variant p.Val1724fs*68/c.5171_5172delTG. Both novel mutations resulted in the premature termination of filamin A with the loss of functional Rod 2 and dimerization region.The present report raised the possibility of the presence of a cardiovascular onset form in the spectrum of FLNA hereditary diseases. The association between SVA and loss-of-function FLNA mutations indicates a unique etiology and pathogenesis among female patients, which requires further investigation to establish the linkage between FLNA variants and a wide spectrum of phenotypes.

Abstract 11343: Unique Phenotypes of Three-Dimensional Aortic Growth in Genetic Aortopathy

Introduction: Patients with genetically-mediated thoracic aortic aneurysm (TAA) are at high risk of progressive aortic growth, although growth is highly variable and often difficult to accurately define using conventional diameter measurements. An emerging image analysis technique, vascular deformation mapping (VDM), provides accurate, three-dimensional (3D) mapping of aortic growth. Hypothesis: 3D growth mapping of the thoracic aorta will reveal unique patterns/phenotypes of growth in patients with genetically-mediated TAA. Material and Methods: We included adult (>18) patients at our center with GM-TAA and at least 2 CT angiograms >1 year apart. 3D aortic growth was measured by VDM. The longest CT interval with was used for analysis. Results: 61 patients (average follow-up 5.4 ± 3.6 years, cumulative 331 years) were included, with etiologies: Marfan (n=41), Loeys-Dietz (n=2), vascular Ehlers-Danlos (n=5), and familial TAA (n=13). Average age was 54.8 ± 16.6 years and 42.6% were female (n=26). The majority (n=38, 62%) had a history of open root/ascending aortic repair. Among post-surgical patients, three patterns emerged from VDM growth maps: 1) “One-and-done” - prior repair of diseased segment with no further aortic growth (n=14); 2) Adjacent segment - growth limited to native aortic segment adjacent to a surgically repaired segment (n=9); 3) Diffuse growth - significant growth involving all native aortic segments (n=15). Among non-surgical patients (n=23, 38%) there were similarly three growth patterns by VDM: 1) Stable - no growth (n=9); 2) Heterogeneous growth - multi-focal growth with intervening regions without growth (n=7); 3) Diffuse growth - contiguous growth involving all segments (n=7). Conclusion: Growth in genetic aortopathy is highly variable in extent and degree both before and after aortic repair. Unique phenotypes of 3D growth identified by VDM may have important implications for risk stratification and surgical planning.

Comprehensive genetic screening for vascular Ehlers-Danlos syndrome through an amplification-based next-generation sequencing system.

Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys-Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

Copper-Binding Domain Variation in a Novel Murine Lysyl Oxidase Model Produces Structurally Inferior Aortic Elastic Fibers Whose Failure Is Modified by Age, Sex, and Blood Pressure.

Lysyl oxidase (LOX) is a copper-binding enzyme that cross-links elastin and collagen. The dominant LOX variation contributes to familial thoracic aortic aneurysm. Previously reported murine Lox mutants had a mild phenotype and did not dilate without drug-induced provocation. Here, we present a new, more severe mutant, Loxb2b370.2Clo (c.G854T; p.Cys285Phe), whose mutation falls just N-terminal to the copper-binding domain. Unlike the other mutants, the C285F Lox protein was stably produced/secreted, and male C57Bl/6J Lox+/C285F mice exhibit increased systolic blood pressure (BP; p < 0.05) and reduced caliber aortas (p < 0.01 at 100mmHg) at 3 months that independently dilate by 6 months (p < 0.0001). Multimodal imaging reveals markedly irregular elastic sheets in the mutant (p = 2.8 × 10−8 for breaks by histology) that become increasingly disrupted with age (p < 0.05) and breeding into a high BP background (p = 6.8 × 10−4). Aortic dilation was amplified in males vs. females (p < 0.0001 at 100mmHg) and ameliorated by castration. The transcriptome of young Lox mutants showed alteration in dexamethasone (p = 9.83 × 10−30) and TGFβ-responsive genes (p = 7.42 × 10−29), and aortas from older C57Bl/6J Lox+/C285F mice showed both enhanced susceptibility to elastase (p < 0.01 by ANOVA) and increased deposition of aggrecan (p < 0.05). These findings suggest that the secreted Lox+/C285F mutants produce dysfunctional elastic fibers that show increased susceptibility to proteolytic damage. Over time, the progressive weakening of the connective tissue, modified by sex and blood pressure, leads to worsening aortic disease.

Multiple Arterial Dissections and Connective Tissue Abnormalities.

Background: Although patients with multiple arterial dissections in distinct arterial regions rarely present with known connective tissue syndromes, we hypothesized that mild connective tissue abnormalities are common findings in these patients. Methods: From a consecutive register of 322 patients with cervical artery dissection (CeAD), we identified and analyzed 4 patients with a history of additional dissections in other vascular beds. In three patients, dermal connective tissue was examined by electron microscopy. DNA from all four patients was studied by whole-exome sequencing and copy number variation (CNV) analysis. Results: The collagen fibers of dermal biopsies were pathologic in all three analyzed patients. One patient carried a CNV disrupting the COL3A1 and COL5A2 genes (vascular or hypermobility type of Ehlers–Danlos syndrome), and another patient a CNV in MYH11 (familial thoracic aortic aneurysms and dissections). The third patient carried a missense substitution in COL5A2. Conclusion: Three patients showed morphologic alterations of the dermal connective tissue, and two patients carried pathogenic variants in genes associated with arterial connective tissue dysfunction. The findings suggest that genetic testing should be recommended after recurrent arterial dissections, independently of apparent phenotypical signs of connective tissue disorders.

An Myh11 single lysine deletion causes aortic dissection by reducing aortic structural integrity and contractility

Pathogenic variants in myosin heavy chain (Myh11) cause familial thoracic aortic aneurysms and dissections (FTAAD). However, the underlying pathological mechanisms remain unclear because of a lack of animal models. In this study, we established a mouse model with Myh11 K1256del, the pathogenic variant we found previously in two FTAAD families. The Myh11∆K/∆K aorta showed increased wall thickness and ultrastructural abnormalities, including weakened cell adhesion. Notably, the Myh11∆K/+ mice developed aortic dissections and intramural haematomas when stimulated with angiotensin II. Mechanistically, integrin subunit alpha2 (Itga2) was downregulated in the Myh11∆K/∆K aortas, and the smooth muscle cell lineage cells that differentiated from Myh11∆K/∆K induced pluripotent stem cells. The contractility of the Myh11∆K/∆K aortas in response to phenylephrine was also reduced. These results imply that the suboptimal cell adhesion indicated by Itga2 downregulation causes a defect in the contraction of the aorta. Consequently, the defective contraction may increase the haemodynamic stress underlying the aortic dissections.

Thoracoabdominal aortic aneurysm in connective tissue disorder patients.

Connective tissue disorders (CTDs) are a group of genetically triggered diseases in which the primary defect involves collagen and elastin protein assembly with potential vascular degenerations such as thoracoabdominal aortic aneurysm (TAAA) and dissection. These most commonly include Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm and dissection. Open surgical repair represents the standard approach in this specific group of patients. Extensive aortic replacements are generally performed in order to reduce long-term complications caused by the progressive dilatation of the remnant aortic segments. In the last decades, endovascular interventions have emerged as a valid alternative in patients affected by degenerative TAAA. However, in patients with CTD, this approach presents higher rates of reinterventions and postoperative complications with a disputable long-term durability, and it is nowadays performed for very selective indications such as severe comorbidities and urgent/emergent settings. Despite a deeper knowledge of the pathophysiological mechanisms involved in CTD, improvements in medical therapy, and a multidisciplinary approach fully involved in the management of these usually frailer patients, this specific group still represents a challenge. Further dedicated studies addressing mid-term and long-term outcomes in this selected population are needed.

Physical activity and health literacy in people with familial thoracic aortic aneurysm and dissection

Physical activity and health literacy in people with familial thoracic aortic aneurysm and dissection

Iris Flocculi Investigated for Familial Thoracic Aortic Aneurysms and Dissections

Slit-lamp examination revealed bilateral iris flocculi (Fig A, right eye; Fig B, left eye), and pigment epithelial excrescences at the pupillary border in a 35-year-old patient. Computed tomography angiography with axial (Fig C) and sagittal (Fig D) views diagnosed a type B aortic aneurysm (right aberrant subclavian artery to infrarenal artery). The patient carried a heterozygous, pathogenic variant in the ACTA2 gene (c.445C>T, p.Arg149Cys) that causes familial thoracic aortic aneurysms and dissections (TAAD).

A novel variant in fibrillin-1 is responsible for early-onset familial thoracic aortic aneurysms in Marfan patients.

BackgroundMarfan syndrome (MFS) is an inherited connective tissue disorder that affects the skeletal, ocular, and cardiovascular system. The disease’s severity and clinical manifestations vary greatly due to pathogenic variants which, combined with a lack of research on the correlation between MFS’s genotype and phenotype, make MFS a challenging disease to diagnose. This study aims to further the understanding of MFS by shedding light on the clinical manifestation of a novel variant in fibrillin-1 (FBN1)—the protein responsible for the genetic defects that lead to MFS.MethodsA patient was diagnosed with MFS by combining a clinical examination (based on the 2010 revision to Ghent nosology criteria) with a targeted next-generation sequence analysis. The functional analysis of the causal mutation and the clinical details of the affected patient were then analyzed.ResultsThe FBN1 heterozygous variant c.5081_5082insT, which is known to delete large fragments from amino acids 1702 to 2871, was found in the proband patient and her son. The two also displayed the skeletal and cardiovascular manifestations of MFS. In addition, the 14-year-old son was identified as having a dilated aortic bulb at the same rupture site of the proband’s dissection, and the proband’s mother also died at age 32 due to aortic dissection.ConclusionsThe FBN1 variant c.5081_5082insT (p.Leu1694fs*9) is a pathogenic mutation that can cause MFS patients to experience early-onset familial thoracic aortic aneurysms (TAA). We hope that this discovery can provide further insight into the treatment of MFS patients with truncating variants in exons 42-65.

Bicuspid Aortic Valve in Infants, Children, and Adolescents: A Review for Primary Care Providers.

1. Talha Niaz, MBBS* 2. Jonathan N. Johnson, MD*,† 3. Frank Cetta, MD*,† 4. Timothy M. Olson, MD*,† 5. Donald J. Hagler, MD*,† 1. *Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, and 2. †Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN * Abbreviations: AHA : : American Heart Association BAV : : bicuspid aortic valve TTE : : transthoracic echocardiography Bicuspid aortic valve is the most common congenital heart defect in children, adolescents, and adults. Primary care providers play an important role in screening, referral, and follow-up of these patients and should be aware of the family screening guidelines, sports participation recommendations, and periodic follow-up requirements for adequate surveillance of the complications that arise from bicuspid aortic valve. After reading this article, readers should be able to: 1. Describe the epidemiology and anatomy of bicuspid aortic valve (BAV). 2. Understand the clinical presentation and diagnosis of BAV in infants, children, and adolescents. 3. Identify the various complications of BAV disease. 4. Discuss the management and follow-up requirements for BAV. 5. Analyze the family screening and sports participation guidelines for patients with BAV. Bicuspid aortic valve (BAV) is the most common congenital heart defect in children, adolescents, and adults. (1) It is a heterogeneous disease that affects both the aortic valve and the aorta. It can lead to many complications, including aortic valve stenosis, regurgitation, or endocarditis. (2)(3) It also can lead to dilation of the aorta, predisposing individuals to a significantly higher risk of aortic aneurysm and dissection. (4) Although most individuals with BAV present with these long-term complications during adulthood, a considerable number of patients may also present during childhood and adolescence with early-onset disease; that may require interventions in up to 12% to 15% of the patients. (5)(6) Therefore, patients with BAV require lifelong follow-up and surveillance. BAV has multiple implications in terms of sports participation and family screening, making it an important subject for primary care providers. This article reviews the anatomy, genetics, presentation, diagnosis, …

Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms

PurposeIn this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. MethodsTrio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. ResultsWe identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. ConclusionA homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.

Abstract 15129: Outcomes Related to Age of Elective Surgery and Age of Dissection Within Genetically Triggered Aneurysm Conditions: The Gentac Experience

Introduction: The GenTAC Registry ( G enetically Triggered T horacic A ortic Aneurysms and Cardiovascular C onditions) followed patients with aortopathies over 8 years among 8 centers with the goal of evaluating cardiovascular outcomes. Methods: Enrollment initiated in 2007, and data were collected until 2015. We included diagnoses with &gt;100 participants: Bicuspid aortic valve with aneurysm (BAV, n=879), Marfan syndrome (MFS, n=861), Familial thoracic aortic aneurysm or dissection (FTAAD, n=378), Other thoracic aortic aneurysm at &lt; 50 years of age (Other&lt;50, n=524), Turner syndrome (TS, n=298), Vascular Ehlers Danlos syndrome (VEDS, n=149), and Loeys-Dietz syndrome (LDS, n=121). We identified patients who underwent elective ascending aortic replacement, total unique dissections, and time to first dissection. With MFS as a reference population and adjusted for sex, endpoints were analyzed by a Firth penalized Cox-PH regression model to account for diagnosis groups with low event numbers. Results: LDS participants at a mean age of (24.5 ± 15.0y) were youngest at elective aortic surgery followed by MFS (32.3 ±12.3y), TS (37.6 ±13.6y), VEDS (35.0 ±SD 7.4y), Other&lt;50 (40.3 ±SD 10.3y), FTAAD (42.9 ±14.2y), and BAV(49.4 ± 13.8 y). Dissections were reported in all diagnosis groups with a total of 472 unique dissections in 3210 patients (14%). Mean age at first dissection was in the third decade for LDS, TS, MFS, VEDS and in the fourth decade for BAV, FTAD, and Other&lt;50. Adjusted hazard ratio for time to first dissection was higher in LDS, 1.77 (95%CI 1.14- 2.77), compared to MFS and other diagnosis groups (Figure 1). Conclusions: Reported aortic dissections were prominent in the GenTAC cohort. Despite elective surgery at a younger age, LDS patients had a higher hazard risk of dissection compared to other diagnosis groups.