Genetic counselling and testing in adults with congenital heart disease: A consensus document of the ESC Working Group of Grown-Up Congenital Heart Disease,the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics
Restricted accessResearch articleFirst published online September, 2020
Genetic counselling and testing in adults with congenital heart disease: A consensus document of the ESC Working Group of Grown-Up Congenital Heart Disease,the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics
Thanks to a better knowledge of the genetic causes of many diseases and an improvement in genetic testing techniques, genetics has gained an important role in the multidisciplinary approach to diagnosis and management of congenital heart disease and aortic pathology. With the introduction of strategies for precision medicine, it is expected that this will only increase further in the future. Because basic knowledge of the indications, the opportunities as well as the limitations of genetic testing is essential for correct application in clinical practice, this consensus document aims to give guidance to care-providers involved in the follow-up of adults with congenital heart defects and/or with hereditary aortic disease. This paper is the result of a collaboration between the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics. Throughout the document, the importance of correct counseling in the process of genetic testing is emphasized, indications and timing for genetic studies are discussed as well as the technical modalities of genetic testing. Finally, the most important genetic diseases in adult congenital heart disease and aortic pathology are also discussed.
StoutKKDanielsCJAboulhosnJA, et al.2018 AHA/ACC guideline for the management of adults with congenital heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol2018; 73(12): e81–e192.
2.
HerskindAMAlmind PedersenDChristensenK. Increased prevalence of congenital heart defects in monozygotic and dizygotic twins. Circulation2013; 128: 1182–1188.
3.
ØyenNPoulsenGBoydHA, et al.Recurrence of congenital heart defects in families. Circulation2009; 120: 295–301.
4.
ZaidiSBruecknerM. Genetics and genomics of congenital heart disease. Circ Res2017; 120: 923–940.
5.
HartmanRJRasmussenSABottoLD, et al.The contribution of chromosomal abnormalities to congenital heart defects: A population-based study. Pediatr Cardiol2011; 32: 1147–1157.
6.
SoemediRWilsonIJBenthamJ, et al.Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am J Hum Genet2012; 91: 489–501.
7.
BreckpotJThienpontBArensY, et al.Challenges of interpreting copy number variation in syndromic and non-syndromic congenital heart defects. Cytogenet Genome Res2011; 135: 251–259.
8.
van EngelenKBaarsMJHFelixJP, et al.The value of the clinical geneticist caring for adults with congenital heart disease: Diagnostic yield and patients’ perspective. Am J Med Genet A2013.
9.
PierpontMEBassonCTBensonDW, et al.American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young. Genetic basis for congenital heart defects: Current knowledge: A scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics. Circulation2007; 115: 3015–3038.
10.
FahedACRobertsAEMitalS, et al.Heart failure in congenital heart disease: A confluence of acquired and congenital. Heart Fail Clin2014; 10: 219–227.
11.
TheisJLZimmermannMTEvansJM, et al.Recessive MYH6 mutations in hypoplastic left heart with reduced ejection fraction. Circ Cardiovasc Genet2015; 8: 564–571.
12.
SchottJJBensonDWBassonCT, et al.Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science1998; 281: 108–111.
13.
HomsyJZaidiSShenY, et al.De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science2015; 350: 1262–1266.
14.
TianYYuanLGossAM, et al.Characterization and in vivo pharmacological rescue of a Wnt2-Gata6 pathway required for cardiac inflow tract development. Dev Cell2010; 18: 275–287.
15.
Mercer-RosaLPintoNYangW, et al.22q11.2 Deletion syndrome is associated with perioperative outcome in tetralogy of Fallot. J Thorac Cardiovasc Surg2013; 146: 868–873.
16.
GillHKSplittMSharlandGK, et al.Patterns of recurrence of congenital heart disease: An analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography. JAC2003; 42: 923–929.
17.
PierpontMEBruecknerMChungWK, et al.American Heart Association Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Genomic and Precision Medicine. Genetic basis for congenital heart disease: Revisited: A scientific statement From the American Heart Association. Circulation2018; 138: e653–e711.
18.
ParrottAWareSM. The role of the geneticist and genetic counselor in an ACHD clinic. Prog Pediatr Cardiol2012; 34: 15–20.
19.
BurchillLGreenwaySSilversidesCK, et al.Genetic counseling in the adult with congenital heart disease: What is the role?Curr Cardiol Rep2011; 13: 347–355.
20.
KearnsWGPenRGrahamJ, et al.Preimplantation genetic diagnosis and screening. Semin Reprod Med2005; 23: 336–347.
21.
European Society of Human Genetics. Statement of the ESHG on direct-to-consumer genetic testing for health-related purposes. Eur J of Hum Genet 2010; 18(12): 1271EP–1273.
22.
HaraksinghRRAbyzovAUrbanAE. Comprehensive performance comparison of high-resolution array platforms for genome-wide Copy Number Variation (CNV) analysis in humans. BMC Genomics2017; 18: 321–321.
23.
MillerDTAdamMPAradhyaS, et al.Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet2010; 86: 749–764.
24.
SouthSTLeeCLambAN, et al.ACMG standards and guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: Revision 2013. Genet Med2013; 15: 901–909.
25.
LaHayeSCorsmeierDBasuM, et al.Utilization of whole exome sequencing to identify causative mutations in familial congenital heart disease. Circ Cardiovasc Genet2016; 9: 320–329.
26.
SifrimAHitzM-PWilsdonA, et al.Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet2016; 48: 1060–1065.
27.
SzotJOCunyHBlueGM, et al.A screening approach to identify clinically actionable variants causing congenital heart disease in exome data. Circ Genom Precis Med2018; 11: e001978–e001978.
28.
ZaidiSChoiMWakimotoH, et al.De novo mutations in histone-modifying genes in congenital heart disease. Nature2013; 498: 220–223.
29.
JinSCHomsyJZaidiS, et al.Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet2017; 49: 1593–1601.
30.
HauserNSSolomonBDVilbouxT, et al.Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital. Mol Genet Genomic Med2018; 6: 200–212.
31.
RenardMFrancisCGhoshR, et al.Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J Am Coll Cardiol2018; 72: 605–615.
32.
MeilhacSMBuckinghamME. The deployment of cell lineages that form the mammalian heart. Nat Rev Cardiol2018; 15: 705–724.
33.
OlsonEN. Gene regulatory networks in the evolution and development of the heart. Science2006; 313: 1922–1927.
34.
DuijnhouwerALBonsLRTimmersHJLM, et al.Aortic dilatation and outcome in women with Turner syndrome. Heart2018; 105(9): 693–700.
35.
CarlsonMAirhartNLopezL, et al.Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: Report of the International Turner Syndrome Aortic Dissection Registry. Circulation2012; 126: 2220–2226.
36.
SilberbachMRoos-HesselinkJWAndersenNH, et al.American Heart Association Council on Cardiovascular Disease in the Young; Council on Genomic and Precision Medicine; and Council on Peripheral Vascular Disease. Cardiovascular Health in Turner Syndrome: A scientific statement from the American Heart Association. Circ Genom Precis Med2018; 11: e000048–e000048.
37.
BonsLRRoos-HesselinkJW. Aortic disease and pregnancy. Curr Opin Cardiol2016; 31: 611–617.
38.
BottoLDMayKFernhoffPM, et al.A population-based study of the 22q11.2 deletion: Phenotype, incidence, and contribution to major birth defects in the population. Pediatrics2003; 112: 101–107.
39.
MorrowBEMcDonald-McGinnDMEmanuelBS, et al.Molecular genetics of 22q11.2 deletion syndrome. Am J Med Genet A2018; 176: 2070–2081.
40.
BaldiniAFulcoliFGIllingworthE. Tbx1: Transcriptional and developmental functions. Curr Top Dev Biol2017; 122: 223–243.
41.
Mercer-RosaLParidonSMFogelMA, et al.22q11.2 Deletion status and disease burden in children and adolescents with tetralogy of Fallot. Circ Cardiovasc Genet2015; 8: 74–81.
42.
van EngelenKTopfAKeavneyBD, et al.22q11.2 Deletion syndrome is under-recognised in adult patients with tetralogy of Fallot and pulmonary atresia. Heart2010; 96: 621–624.
43.
KruszkaPPorrasARde SouzaDH, et al.Williams-Beuren syndrome in diverse populations. Am J Med Genet A2018; 176: 1128–1136.
44.
Morris CA. Williams syndrome. Williams Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al. (eds) GeneReviews® [Internet]. Seattle, WA: University of Washington, 1993–2019 (updated 23 March 2017).
45.
Reamon-BuettnerSMBorlakJ. NKX2-5: An update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD). Hum Mutat2010; 31: 1185–1194.
46.
HarveyRPLaiDElliottD, et al.Homeodomain factor Nkx2-5 in heart development and disease. Cold Spring Harb Symp Quant Biol2002; 67: 107–114.
47.
SteimleJDMoskowitzIP. TBX5: A key regulator of heart development. Curr Top Dev Biol2017; 122: 195–221.
48.
GargVKathiriyaISBarnesR, et al.GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature2003; 424: 443–447.
49.
RobertsAEAllansonJETartagliaM, et al.Noonan syndrome. Lancet2013; 381: 333–342.
50.
MacGroganDMunchJde la PompaJL. Notch and interacting signalling pathways in cardiac development, disease, and regeneration. Nat Rev Cardiol2018; 15: 685–704.
51.
LiLKrantzIDDengY, et al.Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet1997; 16: 243–251.
52.
OdaTElkahlounAGPikeBL, et al.Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet1997; 16: 235–242.
53.
GargVMuthANRansomJF, et al.Mutations in NOTCH1 cause aortic valve disease. Nature2005; 437: 270–274.
54.
PreussCCapredonMWünnemannF, et al.Family based whole exome sequencing reveals the multifaceted role of notch signaling in congenital heart disease. PLoS Genet2016; 12: e1006335–e1006335.
55.
PageDJMiossecMJWilliamsSG, et al.Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of Fallot. Circ Res2019; 124: 553–563.
56.
CocciadiferroDAugelloBDe NittisP, et al.Dissecting KMT2D missense mutations in Kabuki syndrome patients. Hum Mol Genet2018; 27: 3651–3668.
AlbornozGCoadyMARobertsM, et al.Familial thoracic aortic aneurysms and dissections–incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg2006; 82: 1400–1405.
59.
RegaladoESGuoD-CPrakashS, et al.Aortic disease presentation and outcome associated with ACTA2 mutations. Circ Cardiovasc Genet2015; 8: 457–464.
60.
JondeauGRopersJRegaladoE, et al.Montalcino Aortic Consortium. International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet2016; 9: 548–558.
61.
Teixido-TuraGFrankenRGaluppoV, et al.Heterogeneity of aortic disease severity in patients with Loeys-Dietz syndrome. Heart2016; 102(8): 626–632.
62.
KwartlerCSGongLChenJ, et al.Variants of unknown significance in genes associated with heritable thoracic aortic disease can be low penetrant ‘risk variants’. Am J Hum Genet2018; 103: 138–143.
63.
EvangelistaAGallegoPCalvo-IglesiasF, et al.Anatomical and clinical predictors of valve dysfunction and aortic dilation in bicuspid aortic valve disease. Heart2018; 104: 566–573.
64.
Galian-GayLCarro HeviaATeixido-TuraG, et al.Familial clustering of bicuspid aortic valve and its relationship with aortic dilation in first-degree relatives. Heart2019; 105(8): 603–608.
65.
GillisEKumarAALuyckxI, et al.Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor. Front Physiol2017; 8: 13–13.
66.
GouldRAAzizHWoodsCE, et al.ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nat Genet2019; 51: 42–50.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
