Article Text

Cardiogenetics: genetic testing in the diagnosis and management of patients with aortic disease
  1. Prashanth D Thakker,
  2. Alan C Braverman
  1. Cardiovascular Division, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
  1. Correspondence to Dr Alan C Braverman, Cardiovascular Division, Washington University in St Louis School of Medicine, St Louis, MO 63110, USA; abraverm{at}wustl.edu

Abstract

Thoracic aortic aneurysm and aortic dissection have a potent genetic underpinning with 20% of individuals having an affected relative. Heritable thoracic aortic diseases (HTAD) may be classified as syndromic (including Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome and others) or non-syndromic (without recognisable phenotypes) and relate to pathogenic variants in multiple genes affecting extracellular matrix proteins, transforming growth factor-beta (TGF-β) signalling and smooth muscle contractile function. Clinical and imaging characteristics may heighten likelihood of an underlying HTAD. HTAD should be investigated in individuals with thoracic aortic aneurysm or aortic dissection, especially when occurring in younger individuals, in those with phenotypic features and in those with a family history of aneurysm disease. Screening family members for aneurysm disease is important. Consultation with a medical geneticist and genetic testing of individuals at increased risk for HTAD is recommended. Medical management and prophylactic aortic surgical thresholds are informed by an accurate clinical and molecular diagnosis.

  • aortic diseases
  • aortic aneurysm
  • aneurysm
  • dissecting
  • genetics

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Introduction

Thoracic aortic aneurysm (TAA) is an important and actionable risk factor for aortic dissection. While degenerative (atherosclerotic) disease and hypertension (HTN) may cause aneurysm, genetically triggered aortopathies should be considered in individuals with TAA or aortic dissection. Having a first-degree relative with a TAA or aortic dissection is a potent risk factor for aortic dissection.1 2 Approximately 20% of individuals with a TAA will have a family history of aneurysm, inherited in an autosomal dominant pattern that may demonstrate incomplete penetrance and variable expression.3

Heritable thoracic aortic disease (HTAD) encompasses conditions in which aortic disease has an underlying genetic trigger or familial occurrence (table 1). HTAD is classified as syndromic or non-syndromic and relates to pathogenic variants in genes that affect extracellular matrix proteins, signalling pathways and smooth muscle contractile proteins (figure 1). Syndromic HTAD may associate with ocular, craniofacial, musculoskeletal and cutaneous features with a recognisable phenotype, but outward features may be subtle. Individuals with non-syndromic HTADs (nsHTADs) do not display recognisable outward features, and their pattern of inheritance is autosomal dominant with variable expression and incomplete penetrance.4 Population studies demonstrate the familial clustering of TAAs and aortic dissections.1 Heritable aortopathy must especially be considered in younger patients (especially <50 years old) with TAA, in patients with aortic dissection or in patients with a family history of TAA, aortic dissection or cerebral aneurysm.5

Figure 1

Schematic representation elastin lamellae and smooth muscle cells (SMCs) highlighting the proteins that are disrupted by mutations in genes, leading to heritable thoracic aortic disease. Extensions from the elastin lamellae with fibrillin-1–containing microfibrils at the end link to integrin receptors on the cell surface of SMCs. The integrin receptors then link to the contractile filaments inside the cells, thus forming the elastin-contractile unit. Also illustrated is the proteins involved in canonical transforming growth factor (TGF)-β signalling that are disrupted by mutations in the corresponding genes to also lead to heritable thoracic aortic disease. The validated genes predisposing to thoracic aortic disease are shown in red and are adjacent to their corresponding protein. LAP, latency-associated peptide; LTBP, latent transforming growth factor-beta binding protein; MLCK; myosin light chain kinase; MLCP, myosin light chain phosphatase; PK, protein kinase; PKG-1, type I cGMP-dependent protein kinase; RLC, regulatory light chains; aSmad, mothers against decapentaplegic drosophila homologue. Illustration credit: Ben Smith (reproduced with permission from Pinard A, Jones GT, Milewicz DM. Genetics of Thoracic and Abdominal Aortic Diseases. Circ Res. 2019;124:588–606).

Table 1

Heritable thoracic aortic aneurysm conditions

Syndromic heritable thoracic aneurysm disorders

Marfan syndrome (MFS)

MFS is an autosomal dominant condition affecting 1 in 5000 individuals.6 7 The FBN1 gene encodes fibrillin-1, a matrix protein vital to elastin function and important in regulating cellular signalling pathways, and pathogenic variants in FBN1 lead to MFS.6 Phenotypic features include tall stature, joint laxity, dolichostenomaelia, arachnodactyly, pectus abnormalities and scoliosis (table 2). Myopia is common, and ectopia lentis is present in approximately 30%–60% of patients.8 The modified Ghent criteria for diagnosis incorporates family history, FBN1 pathogenic variants, ectopia lentis and the systemic score (tables 2 and 3).7 Pathogenic variants in FBN1 resulting in haploinsufficiency may associate with more severe aortic manifestations than those leading to dominant negative effects.9

Table 2

Revised Ghent criteria systemic score7

Table 3

Revised Ghent diagnostic criteria for the diagnosis of Marfan syndrome7

Patients with MFS develop aortic aneurysm involving the sinuses of Valsalva.7 Distal aortic disease may occur, especially after root replacement.10 Management includes medical therapy and prophylactic surgery to reduce the risk of aortic dissection. Losartan, an angiotensin receptor blocker (ARB), by blocking transforming growth factor-beta (TGF-β) signalling, prevented aneurysms in mouse models and stabilised the aortic root in children with MFS and aggressive aortic disease.11 Trials comparing losartan with atenolol have shown no difference in aortic dilatation rate.12 13 The addition of an ARB to beta blocker may have added benefit.14 15 Treatment with beta blocker and/or ARB is recommended in patients with MFS.16 Prophylactic aortic surgery in MFS is recommended when the aortic size is ≥50 mm or when >45 mm with risk factors, such as family history of dissection, rapid aortic growth (>3 mm/year), significant valvular regurgitation or before pregnancy.16–19

Loeys-Dietz syndrome (LDS)

LDS is an autosomal dominant disorder characterised by aortic (and branch vessel) aneurysm and dissection, arterial tortuosity, craniofacial, musculoskeletal and cutaneous features.20 21 Multiple pathogenic genetic variants altering the TGF-β signalling pathway cause LDS syndrome and TGF-β vasculopathies with overlapping phenotypes informed by the genetic variant (table 1).4

Craniofacial features of LDS include hypertelorism, cleft palate, bifid uvula, bluish sclera and craniosynostosis. Musculoskeletal features include pectus deformities, scoliosis, clubfoot and joint contractures. Cutaneous features may predominate and include translucent skin with visible veins, widened scars, easy bruising and facial milia. Most clinical information is available for TGFBR1 and TGFBR2 pathogenic variants.20–22 In these patients, severe craniofacial involvement associates with earlier onset aortic disease.21 In females with LDS due to pathogenic variants in TGFBR2, low body surface area and severe extra-aortic features may associate with more aggressive aortic disease.22 LDS due to SMAD3 pathogenic variants (also called aneurysms-osteoarthritis syndrome) has early onset osteoarthritis.4 Individuals with TGFB2 pathogenic variants have clinical features overlapping MFS and LDS.23

ARBs ameliorate aortic pathology and prevent aneurysms in murine models of LDS.24 In the absence of clinical trials, beta blockers and ARBs are used. Imaging from head to pelvis is performed to evaluate the entire vascular tree. Prophylactic aortic surgery is recommended when the aortic root or ascending aorta reaches a size of 40–45 mm, depending on specific pathogenic variant, severity of extra-aortic features, age, sex, family history, aortic growth rate and shared decision making.16 17 21 22 Less information is available regarding aortic outcomes and surgical thresholds in those with TGFB2, TGFB3 and SMAD2 pathogenic variants.

Vascular Ehlers-Danlos syndrome (vEDS)

vEDS is due to pathogenic variants in COL3A1 affecting type III procollagen.25 Individuals with vEDS may have translucent skin with visible veins, acrogeria, premature varicose veins and easy bruising. Features also include a ‘pinched nose’, thin lips, attached earlobes, sunken eyes and clubfoot.25 26 vEDS causes vascular and visceral fragility leading to gastrointestinal or uterine rupture and arterial complications. vEDS affects the aorta, visceral arteries, medium calibre aortic branch vessels and cerebral arteries.26 Aortic size is less predictive of vascular complications making management difficult. Genotype–phenotype correlation may inform clinical management. Patients with minimal normal type III procollagen (typically missense pathogenic variants) have a higher risk profile with earlier age of disease onset and incidence of arterial pathology, whereas haploinsufficient (null) variants may lead to a more favourable clinical course with later onset of pathology.25 27

Treatment with celiprolol reported decreased arterial events in vEDS.28 While celiprolol is not FDA approved for use in the USA, other beta blockers are often used in vEDS. Vascular surveillance for asymptomatic dissections and aneurysms is recommended, as repair of arterial pathology could be indicated based on the extent of disease.29 Disorders due to pathogenic variants in other collagen genes are included in online supplemental table 1.

Supplemental material

Other syndromic HTADs

Other disorders with syndromic features that may lead to aortic enlargement include Shprintzen-Goldberg syndrome due to pathogenic variants in SKI, TAA related to pathogenic variants in LOX and the X-linked disorders, arterial tortuosity syndrome due to pathogenic variants in SLC2A10 and Meester-Loeys syndrome (due to pathogenic variants in BGN).4 Pathogenic variants in FLNA, an X-linked disorder, lead to periventricular nodular heterotopia and associate with TAA disease, patent ductus arteriosus and cardiac valve abnormalities.30

Non-syndromic heritable thoracic aneurysm disease

In individuals with unexplained TAA (or dissection) without recognisable syndromic features, there is a 20% incidence of thoracic aortic disease in first-degree relatives.3 nsHTAD, also referred to as familial thoracic aortic aneurysm and dissection, is inherited as an autosomal dominant trait with decreased penetrance and variable expression.4 31 32 Pathogenic variants in genes encoding proteins affecting smooth muscle cell contractile function may lead to TAA and aortic dissection (table 1). The most common genes implicated in nsHTAD include ACTA2, MYH11, MYLK and PRKG1.4 Pathogenic variants in FBN1 and in the TGF-β vasculopathy genes (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 and SMAD2) may also cause nsHTAD.32 Other pathogenic variants in genes leading to HTAD include those in MAT2A, MFAP5 and FOXE3 and THSD4.31–33

Pathogenic variants in ACTA2 are reported in 10%–15% of all nsHTAD, but at a lower frequency in recent studies.4 32 ACTA2 encodes vascular smooth muscle cell-specific actin required for smooth muscle contraction.34 Patients with ACTA2 disease may have livedo reticularis, iris flocculi, premature coronary artery and cerebrovascular disease and are at risk of TAA and aortic dissection.34 Aortic dissections have been described at aortic diameters less than 5 cm. Pathogenic variants in the MYH11 gene cause nsHTAD and associate with patent ductus arteriosus.4 MYLK encodes the myosin light chain kinase that phosphorylases myosin II to assist in contraction of smooth muscle. Pathogenic variants in MYLK may lead to aortic dissection with little or no aortic enlargement.35 PRKG1 encodes cGMP-dependent protein kinase, responsible for smooth muscle cell relaxation. Pathogenic variants in PRKG1 lead to TAA and aortic dissection.36

Management of individuals with nsHTAD involves blood pressure control and vascular surveillance. Beta blockers (and ARBs) are often used. First-degree relatives should be screened for aortic disease, and genetic testing of first-degree relatives should be performed when a pathogenic variant is found in the proband. Even when there is clear evidence of an autosomal dominant transmission of TAA disease in a family, currently available molecular genetic technology only identifies a pathogenic variant in a known gene leading to TAA in about 20%–25% of families. In sporadic TAA disease, genetic variants are found in even fewer cases.4 In the absence of an identified genetic variant, family members should undergo lifelong aortic imaging surveillance when familial TAA is present.

Bicuspid aortic valve disease (BAV)

BAV affects 1%–2% of the population often leads to dilatation of the aortic root or the ascending aorta.37 Haemodynamic alterations due to abnormal aortic flow patterns related to the BAV and/or genetic heterogeneity may underlie aortic dilatation.37 The lifetime risk of aortic dissection in patients with BAV is four to eight times higher than that of the general population, with TAA the major risk factor of aortic dissection.38 BAV and ascending TAA may be familial, inherited as an autosomal dominant disorder with variable expression and incomplete penetrance. While several genetic variants have been identified in patients and families with BAV and TAA (table 1), the vast majority will not have an underlying genetic variant recognised to cause the condition. BAV may occur with familial TAA conditions, and an increased frequency of BAV is occurs in LDS and in certain nsHTAD.38 39 Genetic testing for HTAD may be considered in BAV patients with early onset TAA, familial TAA, root aneurysm and in those with syndromic features.38

Diagnosing patients with HTAD

When evaluating the individual with a dilated aorta or after aortic dissection, a detailed history, family history and careful physical examination are paramount. The physical features may be subtle or unrecognised by the untrained observer. The colour of the sclera, the appearance of the oropharynx, uvula and face, the translucency and elasticity of the skin and appearance of scars, and the appearance of the skeleton, fingers, feet, chest and back must be noted. Inquiring whether any other family members have discriminating features may also assist in identifying a syndromic condition. Geneticists and genetic counsellors have specialised training and expertise in eliciting a complete family history, in recognising subtle features on examination and in the ordering and interpretation of genetic test results. If the provider does not have sufficient training or experience to order and interpret the test results and counsel the patient regarding the test results, referral to a genetics professional is recommended before the test is ordered.40

While TAA disease in younger individuals should trigger an evaluation for genetic aortopathy, the variable expression of these conditions (especially nsHTAD) does not allow an age at presentation for which one can exclude a genetic underpinning. Individuals >60 years of age with HTN may have degenerative aortic disease. Before concluding a degenerative cause for TAA in older individuals, one must first ensure the following: (1) the patient does not have syndromic features; and (2) there is no significant family history (ie, a first or second degree relative with: (A) TAA or dissection, (B) abdominal, branch vessel or cerebral aneurysm, (C) BAV, (D) patent ductus arteriosus or (E) unexplained sudden death below 50 years old).5 In the absence of HTN or other risk factors for TAA in older individuals, screening of first-degree relatives for TAA is recommended. The absolute aortic size (and z-score) and the appearance of the dilated aorta may also increase the likelihood of an underlying genetic or heritable condition (figure 2). When the aorta is dilated to >45 mm or when the aorta is 40–45 mm (or z-score >3), especially when there are dilated sinuses of Valsalva or when present in young individuals (ie, <50 years old) or when associated with a family history of aortic disease, there is more likely to be a HTAD.5 One should analyse imaging for features suggesting underlying genetic aortopathy such as mitral valve prolapse, arterial tortuosity, branch vessel disease and dural ectasia (figure 2). MFS and LDS have aortic root dilatation. nsHTADs may have aortic root and/or ascending aorta dilatation. The occurrence of aortic dissection should trigger an evaluation for a HTAD. A family history of aortic dissection is associated with a sixfold to ninefold increased risk of aortic dissection (in non-syndromic individuals), with a greater risk of dissection when the proband age at dissection is <50 years.1 2 The family history is a potent risk factor for aortic dissection, especially in those with aneurysm disease.41 Therefore, imaging screening for aortic dilatation is recommended for first-degree relatives of the patient with type A aortic dissection regardless of age. Type B aortic dissection may also be the first manifestation of an underlying HTAD, and when a type B aortic dissection (or descending aortic dilatation) is present in individuals without HTN or in those less than 50 years old, evaluation for HTAD is recommended. Among patients with aortic dissection (type A and type B), 11% were discovered to have a pathogenic variant in a TAA gene.42 Those with a pathogenic variant had earlier onset aortic dissection, higher frequency of root aneurysm, less HTN and a higher frequency of a positive family history.42 Features increasing the likelihood of a genetic aetiology for TAA and/or aortic dissection are listed in box 1.

Box 1

Clinical features associated with a genetic predisposition for underlying thoracic aortic aneurysm disease or aortic dissection

  1. Aortic dilatation (especially >45 mm)

    1. Consideration for 40–45 mm (or z-score >3), especially when dilated sinuses of Valsalva, or in the young (<50 years old), or when associated with a +family history (FH).

  2. Aortic dissection (especially <50 years old or <60 years old without HTN)*

  3. Positive family history of TAA or aortic dissection (and/or cerebral aneurysm disease)*

    1. First-degree and/or second-degree relative with:

      1. TAA or aortic dissection.

      2. Aneurysm or dissection in the arterial tree, diagnosed below 50 years old (or <60 years old without HTN).

      3. Bicuspid aortic valve.

      4. Patent ductus arteriosus.

      5. Sudden (unexplained) death below 50 years old.*

  4. Syndromic features

    1. Craniofacial features

      1. Craniosynostosis.

      2. Hypertelorism.

      3. Cleft palate.

      4. Bifid or broad uvula.

      5. Facial features of Marfan syndrome (see table 1).

    2. Ocular features

      1. Lens dislocation.

      2. Iridodenesis.

      3. Retinal detachment.

      4. High myopia (−3 dioptres or higher).

      5. Blue/grey sclera.

      6. Iris flocculi.

    3. Cardiovascular features

      1. MVP.

      2. Arterial tortuosity.

      3. Multiple aneurysms/dissections.

      4. BAV.

      5. PDA.

    4. Musculoskeletal features

      1. Pectus deformities.

      2. Disproportionately elongated fingers, toes, arms and legs.

      3. Joint dislocations, hypermobility or joint contractures.

      4. Severe, early-onset osteoarthritis.

      5. Severe scoliosis or kyphosis.

      6. Lumbosacral dural ectasia.

      7. Clubfoot.

    5. Cutaneous features

      1. Translucent skin with visible veins.

      2. Livedo reticularis.

      3. Abnormal striae not related to weight gain or pregnancy.

      4. Widened, atrophic scars.

      5. Facial milia.

    6. Other features

      1. Spontaneous pneumothorax.

      2. Spontaneous rupture of internal organs.

      3. Recurrent hernias.

  • *There may be a wide variability in the age of onset or recognition of aneurysm disease in heritable thoracic aortic disease and in some families, age of onset may be older than 50 years. BAV, bicuspid aortic valve; FH, family history; HTN, hypertension; MVP, mitral valve prolapse; PDA, patent ductus arteriosus; TAA, thoracic aortic aneurysm.

  • Adapted with permission from: Verhagen et al.5

Figure 2

Imaging features suggesting an underlying genetic aortopathy condition. (A) Transthoracic echocardiogram demonstrating a dilated aortic root (AO) of 4.7 cm and mitral valve prolapse (MVP) in an individual with Marfan syndrome; (B) cerebral angiography demonstrating marked tortuosity of the vertebral artery (arrows) in a patient with Loeys-Dietz syndrome; (C) MRA demonstrating a marked dilated aortic root (AoR) in an individual with an acute type B aortic dissection (arrow) complicating Marfan syndrome; (D) lumbosacral dural ectasia (enlargement of the dural canal) (arrows) in an individual with Marfan syndrome.

When HTAD is present, genetic testing can confirm the diagnosis and allow identification of at-risk relatives (figure 3). For the majority of providers who do not have experience in the evaluation and counselling of individuals based on genetic test results, the specialty genetics service is critically important and genetic counselling before testing is recommended.40 For example, there is often overlap in the phenotypes of syndromic HTADs (especially between MFS and LDS; and among patients with cutaneous features of LDS and those with vEDS). Although rare, ectopia lentis has been reported in LDS.8 In the evaluation of syndromic HTAD, a TAA gene panel is performed to determine if a pathogenic variant is present. In nsHTAD, genetic testing is recommended for individuals with thoracic aortic disease at a young age (especially <50 years old) or when there is a family history of TAA or dissection, cerebral aneurysm or unexplained sudden death (<50 years old) in first-degree or second-degree relatives.

Figure 3

Genetic testing for individuals at risk for heritable thoracic aortic disease (HTAD).1The process of genetic testing differs from traditional laboratory-based testing in that it requires baseline competence in genetic knowledge and practice and typically benefits from interactions between providers and genetics professionals (geneticists or cardiovascular specialists with commensurate genetics experience) and genetic counsellors. (Mital S et al. Circ Cardiovasc Genet. 2016;9:448–467 and Musunuru K et al. Circ Genom Precis Med. 2020;13:e0000067. DOI: 10.1161/HCG.0000000000000067). 2Unless the main provider is sufficiently qualified to choose, order and interpret the genetic testing and, critically, to counsel the patient appropriately as to the importance and meaning of the genetic test results, referral to a genetics professional is indicated before the test is ordered. After the patient has received pretesting genetic counselling, the patient and the provider can make a shared decision as to whether to undergo testing (Musunuru K et al. Circ Genom Precis Med. 2020;13:e0000067. DOI: 10.1161/HCG.0000000000000067). AD, aortic dissection; FDR, first-degree relatives; FH, family history; FTAA, familial thoracic aortic aneurysm; FTAAD, familial thoracic aortic aneurysm and dissection; HTN, hypertension; ICA, intracranial aneurysm; LDS, Loeys-Dietz syndrome; nsHTAD, non-syndromic heritable thoracic aortic disease; SCD, sudden cardiac death at age <50 years old; vEDs, vascular Ehlers-Danlos syndrome. TAA, thoracic aortic aneurysm.

Genetic testing for HTAD involves collecting a buccal swab or blood sample with next-generation sequencing and duplication/deletion testing in a panel of genes. If an individual has features diagnostic for MFS (especially with ectopia lentis) and does not have any features that are unique to LDS, then one can establish the diagnosis of MFS without genetic testing.7 However, many recommend performing targeted genetic testing for confirmation of an FBN1 pathogenic variant. In the absence of ectopia lentis, genetic testing including a panel of genes is recommended for following individuals with TAA disease: (1) in those who have features that may be present in LDS (or not typical for MFS); (2) in those with a positive family history; or (3) in those with syndromic features concerning for genetic aortic disease (see table 1, box 1 and figures 2 and 3). Results of genetic testing may indicate a benign or likely benign variant, a variant that is pathogenic or likely pathogenic, or a variant of unknown significance (VUS) (online supplemental table 2).43 Pathogenic variants that associate with TAA and aortic dissection involve multiple genes including ACTA2, BGN, COL3A1, FBN1, FLNA, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR2 and THSD4. If a genetic diagnosis is confirmed, gene-specific protocols should be used for family screening. Patients with pathogenic variants in genes should be referred to a centre with a medical geneticist, genetic counsellor and cardiologist or other specialist with expertise in genetic aortopathy.40 When a VUS is discovered, it is important to recognise that this result is non-diagnostic and while genetic testing of family members is not be routinely recommended, doing so requires genetics expertise and that such variants may be reclassified in the future to either pathological or more benign, depending on additional information and family segregation.40 44 Only 25% of families with clear evidence of a familial TAA or dissection condition will have a genetic variant identified in one of the known HTAD genes. If no genetic diagnosis is made and if there is a concern for familial TAA, first-degree relatives should begin screening at the age of 25 years or 10 years prior the youngest affected individual in the family.5

Management considerations

Management of individuals with HTAD encompasses lifestyle modification, medications and surgical repair. Lifestyle modifications include physical activity guidelines, smoking cessation, blood pressure control and reproductive considerations. Low level, moderate aerobic exercise and limits on isometric exercise are recommended.45 46 Prophylactic beta blocker and/or ARB therapy are prescribed in normotensive individuals with HTAD and blood pressure control is important for those with HTN.

Family planning in HTAD incorporates contraception management and consultations with a medical geneticist, genetic counsellor, cardiologist and maternal-fetal medicine obstetrician to discuss risks of pregnancy and management during pregnancy. Women with HTAD are at risk of pregnancy-related complications, and recommendations depend on the HTAD, the aortic size and other factors. Pregnancy-related aortic dissection most often occurs in the third trimester or postpartum but may occur throughout pregnancy and may occur after prior root replacement.47

Prophylactic TAA repair to prevent type A aortic dissection is lifesaving in HTAD. The timing of surgical resection is based on expert opinion and is informed by data from large referral centres with most information for MFS, for TGFBR1 and TGFBR2 pathogenic variants and for BAV.18 19 22 48 The data are limited for many HTADs. Because type A dissections may occur at smaller aortic diameters than those in MFS, prophylactic surgery is often recommended at smaller aortic diameters for many non-Marfan HTADs. Using hard lines to guide surgical thresholds is not practical, as some individuals and families have aortic dissection at aortic size thresholds below surgical thresholds, while others have not dissected despite being discovered to have large aneurysms. Recommendations for aortic surgery depend on genetic variant/condition, aortic diameter, rate of aortic growth, family history, age, body size, phenotype, arterial tortuosity, surgical risk and individual choice and requires shared decision making (table 4).

Table 4

Surgical thresholds for aortic root and/or ascending aortic replacement in heritable thoracic aortic aneurysm disease*

Conclusion

TAA and aortic dissection often have an underlying genetic trigger and HTAD should be considered in all individuals with these conditions. Pathogenic variants in multiple genes cause syndromic and non-syndromic HTAD. The likelihood of finding a pathogenic variant leading to the disorder is higher for those with syndromic features, those presenting with disease at age <50 years old and in those with family history of aortic aneurysm, aortic dissection, cerebral aneurysm or unexplained sudden death at a young age. Genetic testing can establish a specific diagnosis in about 25% of cases of familial aortic disease and a genetic diagnosis can guide medical and surgical management. Regardless of whether a specific gene is discovered, screening of family members is important and will identify others with aortic disease in 20% of cases of TAA or dissection.

References

Supplementary materials

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Footnotes

  • Contributors PDT was responsible for initial drafting, revisions, final approval and submission of the manuscript. ACB was responsible for planning, critically revising/adding content and editing the manuscript, and final approval of the manuscript prior to submission.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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