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Chapter 9.2 - Structural heart disease

Genetic influences

from Section 2 - Fetal disease

Published online by Cambridge University Press:  05 February 2013

By
Catherine L. Mercer  and
David I. Wilson
Edited by
Mark D. Kilby ,
Anthony Johnson  and
Dick Oepkes
Mark D. Kilby
Affiliation:
Department of Fetal Medicine, University of Birmingham
Anthony Johnson
Affiliation:
Baylor College of Medicine, Texas
Dick Oepkes
Affiliation:
Department of Obstetrics, Leiden University Medical Center
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Summary

Introduction

Our understanding about the genetic influences on human disease has increased dramatically with the technological developments in genome and DNA analysis and the discovery of the human genome sequence. Whilst much remains unexplained, it is obvious that normal cardiac development is controlled by the genome and there is significant evidence that a proportion of cardiac malformations are caused by genetic factors. This is important for clinicians as an understanding of confirmed genetic factors is essential to estimate recurrence risks of congenital heart disease (CHD) within families and also screen for predicted associated anomalies. An accurate genetic diagnosis can provide important prognostic information for both the initial patient (proband) and other family members, for whom further genetic investigations may be indicated. There is likely to be increased demand for such investigations as improvement in surgical and medical management allows more individuals with CHD to survive to reproductive age and have families of their own. For some the recurrence risk for a cardiac malformation may be as high as 50%; the actual figure varies with different genetic diagnoses. Accurate risk stratification is likely to become increasingly important, and the rapidly developing technologies to detect genetic variation will mean genome-wide investigation will become available in a clinical setting. An aim of this chapter is to introduce clinicians to principles that will help them embrace and understand the results from these investigations and appreciate the implications they will have for their patients.

Birth incidence of congenital heart disease

CHD is one of the commonest human birth defects, with a widely reported birth incidence of just less than 1% [1], and it accounts for one-third of infant deaths that result from congenital malformation. If a broader criteria for CHD is taken that includes any malformation rather than just those with clinical significance (e.g., very small muscular ventricular septal defects [VSDs] or bicuspid aortic valves) the incidence is higher; bicuspid aortic valve is found in ~1–2% of neonates [2]. The incidence of CHD severe enough to require specialized management has remained relatively constant however [3], at around 3/1000 [4].

Keywords

structural heart diseasegene mappinggenetic factorsgenome sequencingDNA sequencebirth defectschromosomal aneuploidy
Type
Chapter
Information
Fetal Therapy
Scientific Basis and Critical Appraisal of Clinical Benefits
 , pp. 113 - 122
Publisher: Cambridge University Press
Print publication year: 2012

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References

Pradat, P, Francannet, C, Harris, JA, Robert, E. The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatr Cardiol 2003;24(3):195–221.Google Scholar
Ransom, J, Srivastava, D. The genetics of cardiac birth defects. Semin Cell Dev Biol 2007;18(1):132–9.Google Scholar
Howitt, G. Atrial septal defect in three generations. Br Heart J 1961;23:494–6.Google Scholar
Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002;39(12):1890–900.Google Scholar
Huang, JB, Liu, YL, Sun, PW, et al. Molecular mechanisms of congenital heart disease. Cardiovasc Pathol 2010;19(5):e183–93.Google Scholar
Gilboa, SM, Correa, A, Botto, LD, et al. Association between prepregnancy body mass index and congenital heart defects. Am J Obstet Gynecol 2010;202(1):51e1–10.Google Scholar
Botto, LD, Lynberg, MC, Erickson, JD. Congenital heart defects, maternal febrile illness, and multivitamin use: a population-based study. Epidemiology 2001;12(5):485–90.Google Scholar
Jenkins, KJ, Correa, A, Feinstein, JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007;115(23):2995–3014.Google Scholar
Zhu, H, Kartiko, S, Finnell, RH. Importance of gene-environment interactions in the etiology of selected birth defects. Clin Genet 2009;75(5):409–23.Google Scholar
Nora, JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic-environmental interaction. Circulation 1968;38(3):604–17.Google Scholar
Schott, JJ, Benson, DW, Basson, CT, et al. Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 1998;281(5373):108–11.Google Scholar
Gebbia, M, Ferrero, GB, Pilia, G, et al. X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 1997;17(3):305–8.Google Scholar
Gong, W, Gottlieb, S, Collins, J, et al. Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J Med Genet 2001;38(12):E45.Google Scholar
Garg, V, Kathiriya, IS, Barnes, R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 2003;424(6947):443–7.Google Scholar
Pizzuti, A, Sarkozy, A, Newton, AL, et al. Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot. Hum Mutat 2003;22(5):372–7.Google Scholar
Sperling, S, Grimm, CH, Dunkel, I, et al. Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Hum Mutat 2005;26(6):575–82.Google Scholar
Reamon-Buettner, SM, Ciribilli, Y, Inga, A, Borlak, J. A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts. Hum Mol Genet 2008;17(10):1397–405.Google Scholar
Wang, B, Yan, J, Peng, Z, et al. Teratocarcinoma-derived growth factor 1 (TDGF1) sequence variants in patients with congenital heart defect. Int J Cardiol 2011;146(2):225–7.Google Scholar
Kosaki, R, Gebbia, M, Kosaki, K, et al. Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet 1999;82(1):70–6.Google Scholar
Kosaki, K, Bassi, MT, Kosaki, R, et al. Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am J Hum Genet 1999;64(3):712–21.Google Scholar
Bamford, RN, Roessler, E, Burdine, RD, et al. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 2000;26(3):365–9.Google Scholar
Garg, V, Muth, AN, Ransom, JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437(7056):270–4.Google Scholar
Robinson, SW, Morris, CD, Goldmuntz, E, et al. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 2003;72(4):1047–52.Google Scholar
Karkera, JD, Lee, JS, Roessler, E, et al. Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans. Am J Hum Genet 2007;81(5):987–94.Google Scholar
Mohapatra, B, Casey, B, Li, H, et al. Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet 2009;18(5):861–71.Google Scholar
Britz-Cunningham, SH, Shah, MM, Zuppan, CW, Fletcher, WH. Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality. N Engl J Med 1995;332(20):1323–9.Google Scholar
Li, DY, Toland, AE, Boak, BB, et al. Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet 1997;6(7):1021–8.Google Scholar
Muncke, N, Jung, C, Rudiger, H, et al. Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation 2003;108(23):2843–50.Google Scholar
Thienpont, B, Zhang, L, Postma, AV, et al. Haploinsufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet 2010;86(6):839–49.Google Scholar
Burn, J, Brennan, P, Little, J, et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 1998;351(9099):311–16.Google Scholar
Grobman, W, Pergament, E. Isolated hypoplastic left heart syndrome in three siblings. Obstet Gynecol 1996;88(4 Pt 2):673–5.Google Scholar
Pease, WE, Nordenberg, A, Ladda, RL. Familial atrial septal defect with prolonged atrioventricular conduction. Circulation 1976;53(5):759–62.Google Scholar
Ferencz, C, Boughman, JA, Neill, CA, Brenner, JI, Perry, LW. Congenital cardiovascular malformations: questions on inheritance. Baltimore-Washington Infant Study Group. J Am Coll Cardiol 1989;14(3):756–63.Google Scholar
Corone, P, Bonaiti, C, Feingold, J, Fromont, S, Berthet-Bondet, D. Familial congenital heart disease: how are the various types related? Am J Cardiol 1983;51(6):942–5.Google Scholar
Wessels, MW, Berger, RM, Frohn-Mulder, IM, et al. Autosomal dominant inheritance of left ventricular outflow tract obstruction. Am J Med Genet A 2005;134A(2):171–9.Google Scholar
Musewe, NN, Alexander, DJ, Teshima, I, Smallhorn, JF, Freedom, RM. Echocardiographic evaluation of the spectrum of cardiac anomalies associated with Trisomy 13 and Trisomy 18. J Am Coll Cardiol 1990;15(3):673–7.Google Scholar
van Egmond, H, Orye, E, Praet, M, Coppens, M, Devloo-Blancquaert, A. Hypoplastic left heart syndrome and 45X karyotype. Br Heart J 1988;60(1):69–71.Google Scholar
van Bon, BW, Mefford, HC, Menten, B, et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 2009;46(8):511–23.Google Scholar
Tartaglia, M, Mehler, EL, Goldberg, R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29(4):465–8.Google Scholar
Zhao, Y, Ransom, JF, Li, A, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1–2. Cell 2007;129(2):303–17.Google Scholar
Hearn, T, Renforth, GL, Spalluto, C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet 2002;31(1):79–83.Google Scholar
Oda, T, Elkahloun, AG, Pike, BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997;16(3):235–4.Google Scholar
Newbury-Ecob, RA, Leanage, R, Raeburn, JA, Young, ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet 1996;33(4):300–7.Google Scholar
Brassington, AM, Sung, SS, Toydemir, RM, et al. Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet 2003;73(1):74–85.Google Scholar
McElhinney, DB, Geiger, E, Blinder, J, Benson, DW, Goldmuntz, E. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 2003;42(9):1650–5.Google Scholar
Carey, AH, Kelly, D, Halford, S, et al. Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. Am J Hum Genet 1992;51(5):964–70.Google Scholar
Mefford, HC, Sharp, AJ, Baker, C, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 2008;359(16):1685–99.Google Scholar
Hillman, K, DeVita, M, Bellomo, R, Chen, J. Meta-analysis for rapid response teams. Arch Intern Med 2010;170(11):996–7; author reply 997.Google Scholar
D’Amours, G, Kibar, Z, Mathonnet, G, et al. Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clin Genet 2011;81(2):128–41.Google Scholar
Lander, ES, Linton, LM, Birren, B, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409(6822):860–921.Google Scholar
Levy, S, Sutton, G, Ng, PC, et al. The diploid genome sequence of an individual human. PLoS Biol 2007;5(10):e254.Google Scholar
Snyder, M, Du, J, Gerstein, M. Personal genome sequencing: current approaches and challenges. Genes Dev 2010;24(5):423–31.Google Scholar

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