Utility of familial screening in non-syndromic thoracic aortic disease

Abstract Background Non-syndromic heritable thoracic aortic disease (nsHTAD) is an autosomal dominant disorder with high mortality rate if undetected. Familial evaluation could be useful to identify high-risk patients early. Purpose To assess the yield of clinical and genetic screening in a cohort of patients with suspected nsHTAD. Methods We collected clinical and genetic data about patients with suspected nsHTAD treated in a specialized clinic. Bicuspid aortic valve cases were excluded. Genetic study was performed with next-generation-sequencing, including at least 30 related genes. All first degree relatives were offered evaluation according to current guidelines. Results Twenty-five index cases were analysed (mean age: 48.3 years, male: 64%). Sixteen patients (64%) presented with acute aortic dissection (postmortem diagnosis was performed in 6 cases with sudden cardiac death). Hypertension was reported in 13 cases (52%) and 8 patients (32%) had smoking history. Family history of aortic aneurysm or dissection was identified in 13 cases (52%). Eighty-three first-degree relatives were evaluated. Clinically affected family members were detected in 10 families (40%). Genetic cause of the disease was identified in 6 families (24%). Table 1 describes main characteristics of index cases with pathogenic variants. Combined clinical and genetic screening was positive in 12 families (48%) and identified 24 relatives (29%) with aortic dilatation or carrier status for the disease. Conclusions The combination of clinical and genetic screening in suspected nsHTAD is a useful tool for early detection of the disease in family members at risk and for the prevention of future complications. FUNDunding Acknowledgement Type of funding sources: None. Table 1

Download Full-text

Screening for Familial Thoracic Aortic Aneurysms with Aortic Imaging Does Not Detect All Potential Carriers of the Disease

Aorta ◽

10.12945/j.aorta.2015.14-052 ◽

2015 ◽

Vol 03 (01) ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Matias Hannuksela ◽

Eva-Lena Stattin ◽

Bengt Johansson ◽

Bo Carlberg

Keyword(s):

Thoracic Aorta ◽

Autosomal Dominant ◽

Aortic Disease ◽

Aortic Aneurysms ◽

Aortic Dilatation ◽

Expected Number ◽

Thoracic Aortic Disease ◽

First Degree Relatives ◽

Number Of Individuals ◽

Second Degree

Background: About 20% of patients with thoracic aortic aneurysm or dissection (TAAD) have a first-degree relative with a similar disease. The familial form (FTAAD) of the disease is inherited in an autosomal-dominant pattern. Current guidelines for thoracic aortic disease recommend screening of first-degree relatives of TAAD patients. In known familial disease, screening of both first- and second-degree relatives is recommended. However, the outcomes of such a screening program are unknown. Methods: We screened all first- and second-degree relatives in seven families with known FTAAD with echocardiography. No underlying gene defect had been detected in these families. Results: Of 119 persons investigated, 13 had known thoracic aortic disease. In the remaining 106 cases, we diagnosed 19 additional individuals with a dilated ascending thoracic aorta; for an autosomal-dominant disease, the expected number of individuals in this group would have been 40 (p<0.0001). Further, only one of the 20 first-degree relatives younger than 40 years had a dilated aorta, although the expected number of individuals with a disease-causing mutation would have been 10. Conclusions: In most families with TAAD, a diagnosis still relies on measuring the diameter of the thoracic aorta. We show that a substantial number of previously unknown cases of aortic dilatation can be identified by screening family members. It is, however, not possible to consider anyone free of the condition, even if the aortic diameter is normal, especially at a younger age.

Download Full-text

Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives

International Journal of Cardiology ◽

10.1016/j.ijcard.2018.01.145 ◽

2018 ◽

Vol 258 ◽

pp. 243-248 ◽

Cited By ~ 13

Author(s):

Judith M.A. Verhagen ◽

Marlies Kempers ◽

Luc Cozijnsen ◽

Berto J. Bouma ◽

Anthonie L. Duijnhouwer ◽

...

Keyword(s):

Aortic Disease ◽

Expert Consensus ◽

Thoracic Aortic Disease ◽

First Degree Relatives ◽

Consensus Recommendations

Download Full-text

KIF6 719Arg Genetic Variant and Risk for Thoracic Aortic Dissection

Aorta ◽

10.12945/j.aorta.2016.16.003 ◽

2016 ◽

Vol 04 (03) ◽

pp. 83-90 ◽

Cited By ~ 8

Author(s):

Olga Iakoubova ◽

Carmen Tong ◽

Joseph Catanese ◽

Charles Rowland ◽

May Luke ◽

...

Keyword(s):

Aortic Aneurysm ◽

Aortic Dissection ◽

Thoracic Aortic Aneurysm ◽

Genetic Variant ◽

The United States ◽

Aortic Disease ◽

Carrier Status ◽

Thoracic Aortic Disease ◽

Logistic Regression Models ◽

Thoracic Aortic Dissection

Background: Carriers of the 719Arg variant in KIF6, compared with noncarriers, have been reported to be at greater risk for coronary heart disease (CHD) in six prospective studies. Because CHD, thoracic aortic dissection, and nondissection thoracic aortic aneurysm share some risk factors and aspects of pathophysiology, we investigated whether carriers of the 719Arg variant also have greater odds of thoracic aortic dissection or nondissected thoracic aortic aneurysm than noncarriers. Methods: We genotyped 140 thoracic aortic dissection cases, 497 nondissection thoracic aortic aneurysm cases, and 275 disease-free controls collected in the United States, Hungary, and Greece and investigated the association between KIF6 719Arg carrier status and thoracic aortic dissection, and between KIF6 719Arg carrier status and nondissection thoracic aortic aneurysm, using logistic regression models adjusted for age, sex, hypertension, smoking, and country. Results: The odds of aortic dissection were two-fold greater in KIF6 719Arg carriers compared with noncarriers (odds ratio (OR) 2.14, 95% confidence interval (CI) 1.18-3.9). To account for the potential of concomitant CHD to confound the association between the KIF6 719Arg and thoracic aortic dissection, we repeated the analysis after removing subjects with concomitant CHD; the estimates for association of KIF6 719Arg carrier status remained essentially the same (OR 2.04, 95% CI 1.11-3.77). In contrast, KIF6 719Arg carrier status was not associated with risk for nondissection thoracic aortic aneurysm. Conclusions: We observed an association of the KIF6 719Arg genetic variant with thoracic aortic dissection in this multicenter case-control study. This association may enhance our management of patients with thoracic aortic disease.

Download Full-text

Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.118.002476 ◽

2019 ◽

Vol 12 (6) ◽

Cited By ~ 10

Author(s):

Brooke N. Wolford ◽

Whitney E. Hornsby ◽

Dongchuan Guo ◽

Wei Zhou ◽

Maoxuan Lin ◽

...

Keyword(s):

Family History ◽

Aortic Dissection ◽

Age Of Onset ◽

Family Members ◽

Aortic Disease ◽

Pathogenic Variant ◽

Carrier Status ◽

Thoracic Aortic Dissection ◽

Pathogenic Variants ◽

History Of

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

Download Full-text

Genetic screening in heritable thoracic aortic disease—rationale, potentials and pitfalls

Indian Journal of Thoracic and Cardiovascular Surgery ◽

10.1007/s12055-020-01124-7 ◽

2021 ◽

Author(s):

Metesh Acharya ◽

Daniele Maselli ◽

Giovanni Mariscalco

Keyword(s):

Genetic Screening ◽

Aortic Disease ◽

Thoracic Aortic Disease

Download Full-text

6127Maternal, fetal and obstetric outcome in patients with thoracic aortic disease: an ancillary analysis of the ROPAC registry

European Heart Journal ◽

10.1093/eurheartj/ehz746.0153 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

L Campens ◽

L Baris ◽

J De Backer ◽

J Roos-Hesselink

Keyword(s):

Aortic Dissection ◽

Ventricular Arrhythmia ◽

Cardiac Disease ◽

Congenital Heart ◽

Aortic Disease ◽

Aortic Dilatation ◽

Thoracic Aortic Disease ◽

Pregnancy And Postpartum ◽

Wide Range ◽

Significant Difference

Abstract Background Cardiovascular disease is the leading cause of death during pregnancy with thoracic aortic dissection being one of the main causes. Thoracic aortic disease (TAD) is most commonly related to hereditary disorders and congenital heart malformations such as bicuspid aortic valve (BAV). Pregnancy is considered as a trigger for aortic complications in women with underlying aortic disease. With this analysis, we aim to study the maternal and fetal outcome of pregnancy in women with TAD. Methods The Registry Of Pregnancy And Cardiac disease (ROPAC) is a large, prospective and global registry and enrolled 4418 women from January 2011 onwards with known cardiac disease (mainly congenital and valvular disease) before pregnancy. Results TAD was present in 217 woman prior to pregnancy. Almost half of them were Marfan patients (MFS), 20% had a BAV, 7.4% Turner syndrome and 23% of patients had no underlying genetic defect or associated congenital heart defect. 35.5% of patients had aortic dilatation of which 6% had an aortic diameter above 45mm. Half of patients had previous pregnancies with no significant difference in parity between woman with and without aortic dilatation. Four patients of which 3 MFS patients had an acute aortic dissection (three type A and one type B aortic dissection) but no lethal (maternal of fetal) events occurred. Two patients presented with ventricular arrhythmia of whom one MFS patient. Caesarian section was not performed significantly more frequent in patients with aortic dilatation. Birth weight was lower in the group of woman with aortic dilatation, related to the use of beta-blocking agents. However, intra-uterine growth retardation and prematurity did not occur more frequently. Conclusion This ancillary analysis of the ROPAC data provides the first large prospective data on pregnancy risk of patients with a wide range of TAD. MFS patients are highly represented in the registry and are a vulnerable group to develop severe complications during pregnancy or peripartum with occurrence of aortic dissection in 3% of patients and ventricular arrhythmia in one. Serial follow-up by a specialized multidisciplinary team throughout pregnancy and postpartum period and patient tailored management of delivery is advised.

Download Full-text

Pregnancy outcome in thoracic aortic disease data from the Registry Of Pregnancy And Cardiac disease

Heart ◽

10.1136/heartjnl-2020-318183 ◽

2021 ◽

pp. heartjnl-2020-318183 ◽

Cited By ~ 1

Author(s):

Laurence Campens ◽

Lucia Baris ◽

Nandita S. Scott ◽

Craig S Broberg ◽

Antione Bondue ◽

...

Keyword(s):

Aortic Dissection ◽

Cardiac Disease ◽

Congenital Heart ◽

Aortic Disease ◽

Fetal Mortality ◽

Aortic Dilatation ◽

Thoracic Aortic Disease ◽

Ehlers Danlos Syndrome ◽

Significant Difference ◽

History Of

BackgroundCardiovascular disease is the leading cause of death during pregnancy with thoracic aortic dissection being one of the main causes. Thoracic aortic disease is commonly related to hereditary disorders and congenital heart malformations such as bicuspid aortic valve (BAV). Pregnancy is considered a high risk period in women with underlying aortopathy.MethodsThe ESC EORP Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective global registry that enrolled 5739 women with pre-existing cardiac disease. With this analysis, we aim to study the maternal and fetal outcome of pregnancy in women with thoracic aortic disease.ResultsThoracic aortic disease was reported in 189 women (3.3%). Half of them were patients with Marfan syndrome (MFS), 26% had a BAV, 8% Turner syndrome, 2% vascular Ehlers-Danlos syndrome and 11% had no underlying genetic defect or associated congenital heart defect. Aortic dilatation was reported in 58% of patients and 6% had a history of aortic dissection. Four patients, of whom three were patients with MFS, had an acute aortic dissection (three type A and one type B aortic dissection) without maternal or fetal mortality. No complications occurred in women with a history of aortic dissection. There was no significant difference in median fetal birth weight if treated with a beta-blocker or not (2960 g (2358–3390 g) vs 3270 g (2750–3570 g), p value 0.25).ConclusionThis ancillary analysis provides the largest prospective data review on pregnancy risk for patients with thoracic aortic disease. Overall pregnancy outcomes in women with thoracic aortic disease followed according to current guidelines are good.

Download Full-text

Colorectal cancer screening behaviors of general surgeons and first-degree family members: a survey-based study

BMC Gastroenterology ◽

10.1186/s12876-019-1106-x ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Suleyman Utku Celik ◽

Hasan Gorkem Cay ◽

Ersin Bayrakdar ◽

Aysima Ince ◽

Esra Nur Ince ◽

...

Keyword(s):

Colorectal Cancer ◽

Family Members ◽

High Volume ◽

Routine Screening ◽

Care Providers ◽

Crc Screening ◽

First Degree Relatives ◽

General Surgeons ◽

Low Volume ◽

Screening Behaviors

Abstract Background Colorectal cancer (CRC) screening rates are low in the general population and among health care providers. The aim of this study was to evaluate the CRC screening practices of general surgeons who provide specialized diagnostic testing and CRC treatment and to examine the CRC screening behaviors of their first-degree family members. Methods A cross-sectional survey was conducted among general surgeons who attended the 21st National Surgical Congress in Turkey held from April 11th to 15th, 2018. The survey included items on demographics, screening-related attitude, CRC screening options, barriers to CRC screening, and surgeons’ annual volumes of CRC cases. Results A total of 530 respondents completed the survey. Almost one-third of the responding surgeons (29.4%, n = 156) were aged over 50 years, among whom approximately half (47.1%, n = 74) reported having undergone CRC screening and preferring a colonoscopy as the screening modality (78.4%). Among general surgeons aged 50 years and older, high-volume surgeons (≥25 CRC cases per year) were more likely to undergo screening compared with low-volume surgeons (< 25 CRC cases per year). The respondents aged below 50 years reported that 56.1% (n = 210) of their first-degree relatives were up-to-date with CRC screening, mostly with colonoscopy. Compared to low-volume surgeons aged below 50 years, high-volume surgeons’ first-degree relatives were more likely to be up-to-date with CRC screening. Conclusion The survey results demonstrated that routine screening for CRC among surgeons and/or their first-degree relatives is currently not performed at the desired level. However, high-volume surgeons are more likely to participate in routine screening.

Download Full-text