The impact of genetic factors and testing on operative indications and extent of surgery for aortopathy

Abstract

Central MessageThe recognition of genetic aortopathy is critically important in the management of aortic disease and management should be tailored based on specific causative genetic variant.See Commentary on page 24.Feature Editor Note—Great strides have been made in understanding the genetic basis of thoracic aortic disease. While many cases do not have a clear heritable pattern, for those that do, knowledge of the genetic basis may have direct implications for management of both the patient and their relatives. Numerous causative genes have been identified for both syndromic and nonsyndromic heritable thoracic aortic disease, and it is expected that many more have yet to be discovered. The patterns of aortic disease associated with each mutation are being investigated, and from this, we are learning that patient management should be gene-specific. For example, the diameter threshold for elective aortic resection and the extent of resection should be tailored not just to the named syndrome but also to the specific gene mutation, when it is known. In the accompanying review, Yang and colleagues explain the current state of genetic testing and its future in the management of both patients and families with heritable thoracic aortic disease.Leora B. Balsam, MD The recognition of genetic aortopathy is critically important in the management of aortic disease and management should be tailored based on specific causative genetic variant. See Commentary on page 24. Thoracic aortic aneurysm affects 5.9 in 100,000 people a year,1Bickerstaff L.K. Pairolero P.C. Hollier L.H. Melton L.J. Van Peenen H.J. Cherry K.J. et al.Thoracic aortic aneurysms: a population-based study.Surgery. 1982; 92: 1103-1108PubMed Google Scholar whereas acute aortic dissection affects 5 to 30 million people a year2Hagan P.G. Nienaber C.A. Isselbacher E.M. Bruckman D. Karavite D.J. Russman P.L. et al.The international registry of acute aortic dissection (IRAD): new insights into an old disease.JAMA. 2000; 283: 897-903Crossref PubMed Scopus (2562) Google Scholar with 20% to 30% of patients with a thoracic aortic aneurysm or dissection (TAAD) having an underlying genetic predisposition.3Milewicz D.M. Regalado E. Heritable thoracic aortic disease overview.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA)2017Google Scholar,4Renard M. Francis C. Ghosh R. Scott A.F. Witmer P.D. Ades L.C. et al.Clinical validity of genes for heritable thoracic aortic aneurysm and dissection.J Am Coll Cardiol. 2018; 72: 605-615Crossref PubMed Scopus (89) Google Scholar To date, variants in more than 30 genes have been implicated in TAAD,5Faggion Vinholo T. Brownstein A.J. Ziganshin B.A. Zafar M.A. Kuivaniemi H. Body S.C. et al.Genes associated with thoracic aortic aneurysm and dissection: 2019 update and clinical implications.Aorta (Stamford). 2019; 7: 99-107Crossref PubMed Scopus (30) Google Scholar with definitive or strong evidence for 11 genes.4Renard M. Francis C. Ghosh R. Scott A.F. Witmer P.D. Ades L.C. et al.Clinical validity of genes for heritable thoracic aortic aneurysm and dissection.J Am Coll Cardiol. 2018; 72: 605-615Crossref PubMed Scopus (89) Google Scholar Heritable thoracic aortic disease (HTAD) can be syndromic—associated with additional systemic features, such as Marfan syndrome (MFS) or Loeys–Dietz syndrome (LDS)—or nonsyndromic, as with ACTA2, MYLK, and MYH11 mutations.6Pomianowski P. Elefteriades J.A. The genetics and genomics of thoracic aortic disease.Ann Cardiothorac Surg. 2013; 2: 271-279PubMed Google Scholar Although all variants in causative genes are known as heritable thoracic disease, each gene mutation behaves differently, resulting in varying clinical courses. Identification of patients at risk and understanding of the pathology and clinical course of each mutation can facilitate clinical decision-making and improve outcomes in TAAD. In this review, we uniquely (1) discuss the strategy of managing each aortopathy based on the individual gene mutations instead of the named syndromes; (2) incorporate the latest publications, such as sex differences in patients with TGFBR1 mutations and the difference in aortic events between SMAD3 mutations and TGFBR1 and TGFBR2 mutations despite being under the LDS umbrella term; (3) discuss the management of these patients from a surgical standpoint, both when to operate based on specific gene mutations and how much to resect in the initial elective surgery or emergent acute type A dissection repair to prevent future complications and reoperations; and (4) provide a comprehensive list of Clinical Laboratory Improvement Amendments–certified genetic tests, respective company, and what genes are analyzed with each test respectively. The majority of causative variants categorized as HTAD have been identified in genes that encode proteins of the extracellular matrix, involved in vascular smooth muscle contraction and metabolism, and transforming growth factor-β signaling pathways that are essential to the integrity of the aortic wall.5Faggion Vinholo T. Brownstein A.J. Ziganshin B.A. Zafar M.A. Kuivaniemi H. Body S.C. et al.Genes associated with thoracic aortic aneurysm and dissection: 2019 update and clinical implications.Aorta (Stamford). 2019; 7: 99-107Crossref PubMed Scopus (30) Google Scholar,7Pinard A. Jones G.T. Milewicz D.M. Genetics of thoracic and abdominal aortic diseases.Circ Res. 2019; 124: 588-606Crossref PubMed Scopus (117) Google Scholar MFS, LDS, and vascular Ehlers–Danlos syndrome (vEDS) primarily comprise syndromic HTAD with mutations in FBN1, TGFBR1 and TGFBR2, and COL3A1, respectively, with other syndromic TAAD having been reported, although less prevalent and with less cardiovascular burden.8Fletcher A.J. Syed M.B.J. Aitman T.J. Newby D.E. Walker N.L. Inherited thoracic aortic disease: new insights and translational targets.Circulation. 2020; 141: 1570-1577Crossref PubMed Scopus (15) Google Scholar, 9Rohde S. Zafar M.A. Ziganshin B.A. Elefteriades J.A. Thoracic aortic aneurysm gene dictionary.Asian Cardiovasc Thorac Ann. 2020; https://doi.org/10.1177/0218492320943800Crossref Scopus (3) Google Scholar, 10Ostberg N.P. Zafar M.A. Ziganshin B.A. Elefteriades J.A. The genetics of thoracic aortic aneurysms and dissection: a clinical perspective.Biomolecules. 2020; 10: 182Crossref Scopus (30) Google Scholar Other systemic features of syndromic TAAD often include involvement of the musculoskeletal, ocular, cutaneous, and integumentary systems among others such as joint laxity, long bone overgrowth, ectopia lentis, pectus deformity, scoliosis, skin striae, etc. MFS is an autosomal-dominant connective tissue disorder that results from mutations in FBN1, the gene for fibrillin-1 (an essential component of the extracellular matrix), which results in skeletal (long bone overgrowth, joint laxity, vertebral column deformity), ocular (lens displacement, myopia), and cardiovascular (aortic root aneurysm and dissection, mitral valve prolapse) abnormalities, among others. The cardiovascular abnormalities, specifically aortic dissection and rupture, are the leading cause of morbidity and mortality.11Groth K.A. Stochholm K. Hove H. Andersen N.H. Gravholt C.H. Causes of Mortality in the Marfan syndrome (from a nationwide register study).Am J Cardiol. 2018; 122: 1231-1235Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar LDS is an autosomal-dominant connective tissue disorder that results from mutations in TGFBR1, TGFBR2, SMAD3, TFGB2, and TGFB3, which encode proteins of the TGF-β signaling pathway, a critical pathway in blood vessel development and vascular maintenance.3Milewicz D.M. Regalado E. Heritable thoracic aortic disease overview.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA)2017Google Scholar,10Ostberg N.P. Zafar M.A. Ziganshin B.A. Elefteriades J.A. The genetics of thoracic aortic aneurysms and dissection: a clinical perspective.Biomolecules. 2020; 10: 182Crossref Scopus (30) Google Scholar Patients with LDS exhibit many overlapping features with MFS (joint laxity, pectus, joint laxity, long bone overgrowth) and vEDS (easy bruising, thin skin); however, craniofacial features such as ocular hypertelorism, bifid uvula/cleft palate, and cervical spine instability are unique to LDS.3Milewicz D.M. Regalado E. Heritable thoracic aortic disease overview.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA)2017Google Scholar In addition, aortic disease in LDS tends to be more severe and aggressive, with aortic dissection and rupture at younger ages and smaller aortic diameters and more widespread vasculopathy, with aneurysms being more widespread and not limited to the aorta as in MFS.3Milewicz D.M. Regalado E. Heritable thoracic aortic disease overview.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA)2017Google Scholar,4Renard M. Francis C. Ghosh R. Scott A.F. Witmer P.D. Ades L.C. et al.Clinical validity of genes for heritable thoracic aortic aneurysm and dissection.J Am Coll Cardiol. 2018; 72: 605-615Crossref PubMed Scopus (89) Google Scholar,12Loeys B.L. Chen J. Neptune E.R. Judge D.P. Podowski M. Holm T. et al.A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.Nat Genet. 2005; 37: 275-281Crossref PubMed Scopus (1277) Google Scholar vEDS is an autosomal-dominant connective tissue disorder that results from mutations in COL3A1, the gene for pro-alpha1 chains of type III collagen (the major structural component of large blood vessels).8Fletcher A.J. Syed M.B.J. Aitman T.J. Newby D.E. Walker N.L. Inherited thoracic aortic disease: new insights and translational targets.Circulation. 2020; 141: 1570-1577Crossref PubMed Scopus (15) Google Scholar vEDS has the worst prognosis of all EDS subtypes and is characterized by abnormalities of the skin and joints as well as arterial, intestinal, and uterine fragility, with arterial dissection or rupture being the most common cause of death, including the thoracic or abdominal aorta.13Pepin M. Schwarze U. Superti-Furga A. Byers P.H. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.N Engl J Med. 2000; 342: 673-680Crossref PubMed Scopus (938) Google Scholar Nonsyndromic HTAD, isolated cardiovascular findings without systemic features, is a heterogeneous cohort of patients in which the underlying genetic causes include mutations in ACTA2, MYH11, MYLK, PRKG1, LOX, FOXE3, MAT2A, MFAP5, BGN, ELN, NOTCH1, and COL5A1, among others, in addition to FBN1, FBN2, TGFBR1, TGFBR2, SMAD3, TFGB2, TGFB3, and COL3A1, which can be syndromic or nonsyndromic,3Milewicz D.M. Regalado E. Heritable thoracic aortic disease overview.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA)2017Google Scholar with definitive or strong for variants in ACTA2, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK, LOX, and PRKG14Renard M. Francis C. Ghosh R. Scott A.F. Witmer P.D. Ades L.C. et al.Clinical validity of genes for heritable thoracic aortic aneurysm and dissection.J Am Coll Cardiol. 2018; 72: 605-615Crossref PubMed Scopus (89) Google Scholar (Table 1). In patients with nonsyndromic TAAD, up to 20% have a strong family history—termed familial thoracic aortic aneurysm and dissection, with up to 30% of nonsyndromic HTAD having a causative pathogenic variant in one of the known HTAD-related genes. The underlying gene in which the pathogenic mutation is located can predispose to a certain phenotype, for example, patients with pathogenic variants in PRKG1 present with aortic dissection relatively early in life and at smaller aortic diameters.14Gago-Diaz M. Blanco-Verea A. Teixido G. Huguet F. Gut M. Laurie S. et al.PRKG1 and genetic diagnosis of early-onset thoracic aortic disease.Eur J Clin Invest. 2016; 46: 787-794Crossref Scopus (16) Google ScholarTable 1Genes with strong or definitive evidence associated with syndromic and nonsyndromic heritable thoracic aortic diseaseHeritable thoracic aortic diseaseAssociated genesSyndromic Marfan syndromeFBN1 Loeys–Dietz syndromeTGFBR1, TGFBR2, TGFB2, SMAD3 Vascular Ehlers–Danlos syndromeCOL3A1NonsyndromicACTA2, MYLK, MYH11, PRKG1, LOX Open table in a new tab Bicuspid aortic valve (BAV) is a heterogenous disorder with associated aortopathy and despite established heritability, specific causative variants remain unsubstantiated. Genes with the most extensive evidence are NOTCH1, GATA factors (GATA4, GATA5, GATA6), KROX22, and ROBO4; however, all of the variants combined account for a small percentage of BAV cases and the mutations are yet to be identified in the majority of BAV cases.15Jiao J. Xiong W. Wang L. Yang J. Qiu P. Hirai H. et al.Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves.EBioMedicine. 2016; 10: 282-290Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 16Norton E. Yang B. Managing thoracic aortic aneurysm in patients with bicuspid aortic valve based on aortic root-involvement.Front Physiol. 2017; 8: 397Crossref PubMed Scopus (15) Google Scholar, 17Laforest B. Andelfinger G. Nemer M. Loss of Gata5 in mice leads to bicuspid aortic valve.J Clin Invest. 2011; 121: 2876-2887Crossref PubMed Scopus (133) Google Scholar, 18Gharibeh L. Komati H. Bosse Y. Boodhwani M. Heydarpour M. Fortier M. et al.GATA6 regulates aortic valve remodeling, and its haploinsufficiency leads to right-left type bicuspid aortic valve.Circulation. 2018; 138: 1025-1038Crossref PubMed Scopus (38) Google Scholar, 19Yang B. Zhou W. Jiao J. Nielsen J.B. Mathis M.R. Heydarpour M. et al.Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.Nat Commun. 2017; 8: 15481Crossref PubMed Scopus (58) Google Scholar, 20Gould R.A. Aziz H. Woods C.E. Seman-Senderos M.A. Sparks E. Preuss C. et al.ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.Nat Genet. 2019; 51: 42-50Crossref PubMed Scopus (61) Google Scholar Mutations in NOTCH1 and ROBO4 have the most evidence and could be associated with BAV; however, clinical decisions are not based on genetic variants in BAV since the association is not strong and there are no genetic tests. Patients with BAV can be classified clinically into 2 subtypes based on valvulopathy and aortopathy as we presented previously16Norton E. Yang B. Managing thoracic aortic aneurysm in patients with bicuspid aortic valve based on aortic root-involvement.Front Physiol. 2017; 8: 397Crossref PubMed Scopus (15) Google Scholar: (a) malignant form—root aneurysm and aortic insufficiency—and (b) benign form—ascending aneurysm and aortic stenosis and could be treated with a more aggressive and conservative approach, respectively. Patients with BAV can be managed based on phenotype as well as family history. For patients with BAV we recommend an elective operation for thoracic aortic aneurysm (root/ascending) at 5 cm for patients with a family history of aortic dissection. Advances over the past 20 years have led to increased discovery and understanding of genetic and molecular mechanisms involved in TAAD, with the number of causative variants increasing with time; however, many still lack evidence or remain undiscovered. Although a majority of TAAD are degenerative in nature with hypertension as the major risk factor, genetic predisposition is the second major risk factor.7Pinard A. Jones G.T. Milewicz D.M. Genetics of thoracic and abdominal aortic diseases.Circ Res. 2019; 124: 588-606Crossref PubMed Scopus (117) Google Scholar,21Milewicz D.M. Ramirez F. Therapies for thoracic aortic aneurysms and acute aortic dissections.Arterioscler Thromb Vasc Biol. 2019; 39: 126-136Crossref PubMed Scopus (43) Google Scholar Genetics are a crucial piece in determining clinical management of TAAD. Guidelines for when to pursue surgical intervention are primarily based on aortic diameter criteria; however, diameter ranges indicating a need for surgical repair vary based on etiology. The American Heart Association/American College of Cardiology guidelines22Hiratzka L.F. Bakris G.L. Beckman J.A. Bersin R.M. Carr V.F. Casey Jr., D.E. et al.2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease.Circulation. 2010; 121: e266-e369Crossref PubMed Scopus (1800) Google Scholar recommend that patients with genetically mediated aneurysms undergo elective surgical repair at an ascending or aortic root diameter of 4.0 to 5.0 cm, depending on the condition. However, underlying genetic etiology often is unknown at time of presentation with TAAD, and the identification of pathogenic genetic variants have the potential to improve management and direct treatment strategies. A recent study by our group23Wolford B.N. Hornsby W.E. Guo D. Zhou W. Lin M. Farhat L. et al.Clinical implications of identifying pathogenic variants in individuals with thoracic aortic dissection.Circ Genom Precis Med. 2019; 12: e002476Crossref PubMed Scopus (26) Google Scholar identified pathogenic variants in 10.8% of patients with a history of thoracic aortic dissection, with pathogenic variants identified in COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2. In addition, age <50 years, no history of hypertension, and family history of aortic disease were significantly associated with pathogenic variant carriers23Wolford B.N. Hornsby W.E. Guo D. Zhou W. Lin M. Farhat L. et al.Clinical implications of identifying pathogenic variants in individuals with thoracic aortic dissection.Circ Genom Precis Med. 2019; 12: e002476Crossref PubMed Scopus (26) Google Scholar; therefore, young patients (<50 years old) with a family history and without hypertension should undergo genetic testing. Similarly, Verhagen and colleagues24Verhagen J.M.A. Kempers M. Cozijnsen L. Bouma B.J. Duijnhouwer A.L. Post J.G. et al.Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives.Int J Cardiol. 2018; 258: 243-248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar recommend genetic testing in patients with a thoracic aortic aneurysm ≥45 mm or dissection and (1) age at diagnosis <50 years, or (2) age at diagnosis 50-60 years and no hypertension, or (3) positive family history, of (4) presence of syndromic features.24Verhagen J.M.A. Kempers M. Cozijnsen L. Bouma B.J. Duijnhouwer A.L. Post J.G. et al.Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives.Int J Cardiol. 2018; 258: 243-248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar If the patient has a pathogenic variant, either syndromic or nonsyndromic, then their family should be tested. In nonsyndromic HTAD, first- and second-degree relatives of patients with familial nonsyndromic HTAD and first-degree relatives of patients with sporadic nonsyndromic HTAD should be screened.25Mariscalco G. Debiec R. Elefteriades J.A. Samani N.J. Murphy G.J. Systematic review of studies that have evaluated screening tests in relatives of patients affected by nonsyndromic thoracic aortic disease.J Am Heart Assoc. 2018; 7: e009302Crossref PubMed Scopus (21) Google Scholar HTAD is a genetically heterogeneous disease: clinical manifestations overlap with many different gene mutations, and current sequencing techniques make it possible to sequence multiple genes within a short period of time at an affordable cost; therefore, testing of aortopathy gene panel should be conducted. Current aortopathy panels vary in genes they analyze, analyzing 4-52 genes depending on the company (Table 2). Milewicz and Regalado3Milewicz D.M. Regalado E. Heritable thoracic aortic disease overview.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA)2017Google Scholar suggest genetic panels include some or all of 16 genes known to predispose to TAAD: ACTA2, BGN, COL3A1, FBN1, FOXE3, LOX, MAT2A, MFAP5, MYH11, MYLK, PRKG1, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2. ACTA2, FBN1, MYH11, SMAD3, TGFBR1, and TGFBR2 are included in >90% of available panels (Table 3). If a high-risk, young patient returns a negative panel, additional testing such as whole-exome sequencing, genome-wide screening,26Demo E. Rigelsky C. Rideout A.L. Graf M. Pariani M. Regalado E. et al.Genetics and precision medicine: heritable thoracic aortic disease.Med Clin North Am. 2019; 103: 1005-1019Abstract Full Text Full Text PDF Scopus (5) Google Scholar and copy-number vibration analysis27Overwater E. Marsili L. Baars M.J.H. Baas A.F. van de Beek I. Dulfer E. et al.Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders.Hum Mutat. 2018; 39: 1173-1192Crossref PubMed Scopus (22) Google Scholar may be indicated. In addition, testing could result in identification of a variant of unknown significance or a pathogenic variant in a gene not yet identified. Even if all genetic testing is negative, all first-degree family members should undergo aortic imaging to rule out thoracic aortic disease,23Wolford B.N. Hornsby W.E. Guo D. Zhou W. Lin M. Farhat L. et al.Clinical implications of identifying pathogenic variants in individuals with thoracic aortic dissection.Circ Genom Precis Med. 2019; 12: e002476Crossref PubMed Scopus (26) Google Scholar because there are many pathogenic variants not discovered yet. Clinical genetic testing may help to prevent devastating events, such as thoracic aortic dissections and death, for patients and family members of pathogenic variant carriers who are high risk but have yet to develop the aortopathy.Table 2Genetic testing for heritable thoracic aortic diseaseNameNumber of genesGenetic panel genesTurnaround time1Invitae Aortopathy Comprehensive Panel∗Add-on Preliminary-evidence Gene for Aortopathy; HCN4, MAT2A, SMAD6.24ACTA2, CBS, COL3A1, COL5A1, COL5A2, EFEMP2, FBN1, FBN2, FLNA, FOXE3, MED12, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR210-21 calendar days (14 d on average)2ARUP Aortopathy Panel21ACTA2, CBS, COL3A1, COL5A1, COL5A2, EFEMP2, FBN1, FBN2, FLNA, LOX,†Deletion/duplication detection not available for this gene. MYH11, MYLK, PLOD1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR23-6 wk3OHSU Knight Diagnostic Laboratories Familial Aneurysm and Aortopathy Panel31ACTA2, ADAMTS2, B3GALT6, B4GALT7, CBS, CHST14, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FKBP14, FLNA, MED12, MYH11, MYLK, NOTCH1, PLOD1, PRDM5, SKI, SLC2A10, SLC39A13, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2, TNXB, ZNF4694Blueprint Genetics Aorta Panel52ABCC6,‡Some, or all, of the gene is duplicated in the genome. ABL1, ACTA2, ADAMTS10, ADAMTS17, ADAMTS2,§The gene has suboptimal coverage (means <90% of the gene's target nucleotides are covered at >20× with mapping quality score (MQ >20) reads), and/or the gene has exons listed under test limitations section that are not included in the panel, as they are not sufficiently covered with high-quality sequence reads. ‡ or §The sensitivity to detect variants may be limited in these genes. ADAMTSL4, ALDH18A1, ATP7A, B3GAT3,‡Some, or all, of the gene is duplicated in the genome.,§The gene has suboptimal coverage (means <90% of the gene's target nucleotides are covered at >20× with mapping quality score (MQ >20) reads), and/or the gene has exons listed under test limitations section that are not included in the panel, as they are not sufficiently covered with high-quality sequence reads. ‡ or §The sensitivity to detect variants may be limited in these genes. BGN, CBS, COL1A1, COL1A2, COL2A1, COL3A1, COL4A5, COL5A1, COL5A2, COLGALT1, EFEMP2, ELN, ENPP1, FBLN5, FBN1, FBN2, FKBP14, FLNA, FOXE3, GATA5, HCN4, LOX, MAT2A,‡Some, or all, of the gene is duplicated in the genome. MED12, MFAP5, MYH11, MYLK,‡Some, or all, of the gene is duplicated in the genome. NOTCH1, PLOD1, PRKG1, SKI, SLC2A10, SLC39A13, SMAD2, SMAD3, SMAD4, SMAD6, TGFB2, TGFB3, TGFBR1, TGFBR2, ZDHHC94 wk5labcorp GeneSec: Cardio-Familial Aortopathy Panel10ACTA2, COL3A1, FBN1, MYH11, MYLK, SLC2A10, SMAD3, TGFB2, TGFBR1, TGFBR218-24 d6GeneDx Marfan/TAAD Panel26ACTA2, BGN, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, LOX, MAT2A, MED12, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD2, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR24 wk7AmbryGenetics TAADNext35ACTA2, BGN, CBS, CHST14, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, EFEMP2, FBN1, FBN2, FKBP14, FLNA, FOXE3, LOX, MAT2A, MED12, MFAP5, MYH11, MYLK, NOTCH1, PLOD1, PRDM5, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR2, TNXB, ZNF46914-21 d8PreventionGenetics Familial Thoracic Aortic Aneurysm and Dissection Panel17ACTA2, COL3A1, FBN1, FOXE3, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR218 d on average9Collagen Diagnostic Lab Arterial Aneurysm Panel25ACTA2, BGN, CBS, COL1A1, COL3A1, FBN1, FBN2, FOXE3, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PLOD3, PRKG1, SKI, SLC2A10, SMAD2, SMAD3, SMAD4, SMAD6, TGFB2, TGFB3, TGFBR1, TGFBR210FulgentGenetics Marfan Syndrome and TAAD Panel33ACTA2, BGN, CBS, COL3A1, COL5A1, COL5A2, EFEMP2, ELN, FBN1, FBN2, FLNA, FOXE3, HCN4, LOX, MAT2A, MED12, MFAP5, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, SKI, SLC2A10, SMAD2, SMAD3, SMAD4, SMAD6, TAB2, TGFB2, TGFB3, TGFBR1, TGFBR23-5 wk11EGL Genetics Marfan Syndrome, TAAD, and Related Disorders Panel17ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1, TGFBR26 wk12Transgenomic Marfan Syndrome and Aortic Aneurysm Panel4ACTA2, FBN1, TGFBR1, TGFBR24-6 wk13Evicore TAAD Panel23ACTA2, CBS, COL3A1, COL5A1, COL5A2, EFEMP2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR214Connective Tissue Gene Tests Marfan Syndrome, Loeys–Dietz Syndrome, Familial TAAD, and Related Disorders Panel28ACTA2, BGN, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, FOXE3, LOX, LTBP3, MAT2A, MED12, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD2, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR22-4 wk15Mayo Clinic Laboratories Marfan Syndrome and Related Disorders Multi-Gene Panel21ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR22-4 wk16Asper Cardiogenetics Familial TAAD and Related Syndromes NGS Panel19ACTA2, BGN, COL3A1, COL5A1, FBN1, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SLC2A10, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR36-9 wk17CeGaT EDS, MFS, LDS, Aortic Aneurysm and Differential Diagnoses49ABCC6, ACTA2, ACVR1, ADAMTS2, ALDH18A1, ATP6V0A2, ATP6V1A, ATP6V1E1, B3GALT6, B4GALT7, BGN, C1R, C1S, CBS, CHST14, COL1A1, COL1A2, COL3A1, COL4A1, COL5A1, COL5A2, DSE, EFEMP2, ELN, FBLN5, FBN1, FBN2, FKBP14, FOXE3, GORAB, LOX, LTBP4, MFAP5, MYH11, MYLK, PLOD1, PRDM5, PYCR1, SKI, SLC2A10, SLC39A13, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR2, TNXB, ZNF4694-6 wk18Color Hereditary Heart HealthǁSeveral regions that cannot be reliably assessed with standard target enrichment protocols are not analyzed: KCNH2 exon 4, KCNQ1 exon 1, and TGFBR1 exon 1. In APOB, only positions known to impact familial hypercholesterolemia risk are analyzed: only chr2:g.21229159_21229161 (APOB codon 3527) is analyzed. For the LDLR promoter region, the detection of deletions, duplications, and complex structural rearrangements may be limited.References/Links to Panels1.https://www.invitae.com/en/physician/tests/02301/#info-panel-assay_information.2.https://ltd.aruplab.com/Tests/Pub/2006540.3.https://www.ohsu.edu/lab-services/familial-aneurysm-and-aortopathy-panel.4.https://blueprintgenetics.com/tests/panels/cardiology/aorta-panel/.5.https://www.labcorp.com/tests/451432/geneseq-cardio-familial-aortopathy-profile.6.https://www.genedx.com/wp-content/uploads/2018/04/Info_Sheetcardio_Marfan-TAAD_update-2_20_20.pdf.7.https://www.ambrygen.com/providers/genetic-testing/12/cardiology/taadnext.8.https://www.preventiongenetics.com/testInfo?val=Familial+Thoracic+Aortic+Aneurysm+and+Dissection+%28TAAD%29+Panel.9.http://uwcpdx.org/core-familial-aneurysm-panel/.10.https://www.fulgentgenetics.com/marfan-taad.11.https://www.egl-eurofins.com/tests/MM099.12.http://www.transgenomic.com/labs/cardiology/familion/marfan-taad.html.13.https://www.evicore.com/-/media/files/evicore/clinical-guidelines/solution/lab-management/healthplan/test-specific-guidelines/taad_panel_testing_2020_v2.pdf.14.https://www.ctgt.net/panel/marfan-syndrome-loeys-dietz-syndrome-familial-thoracic-aortic-aneurysms-dissections-and.15.https://www.mayocliniclabs.com/test-catalog/Performance/63029.16.https://www.asperbio.com/asper-cardiogenetics/familial-thoracic-aortic-aneurysm-and-dissection-and-related-syndromes-ngs-panel.17.https://www.cegat.de/en/diagnostics/diagnostic-panels/connective-tissue-diseases/#CTD02.18.https://support.color.com/en/articles/2393820-what-is-the-color-hereditary-heart-health-test19.https://www.ddccliniclab.org/test/detail/familial-thoracic-aortic-aneurysms-ngs-panel.30ACTA2, ACTC1, APOB, COL3A1, SC2, DSG2, DSP, FBN1, GLA, KCNH2, KCNQ1, LDLR, LMNA, MYBPC3, MYH7, MYH11, MYL2, MYL3, PCSK9, PKP