Structural heart disease

doi:10.1017/CBO9780511997778.013

Chapter 9.2 - Structural heart disease

Genetic influences

from Section 2 - Fetal disease

Published online by Cambridge University Press: 05 February 2013

Catherine L. Mercer and

Edited by

Anthony Johnson and

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

Book contents

Get access

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 disease gene mapping genetic factors genome sequencing DNA sequence birth defects chromosomal aneuploidy

Type: Chapter
Information: Fetal Therapy
Scientific Basis and Critical Appraisal of Clinical Benefits
, pp. 113 - 122

DOI: https://doi.org/10.1017/CBO9780511997778.013 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

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

Book contents

Chapter 9.2 - Structural heart disease

Summary

Keywords

Access options

References

Save book to Kindle

Save book to Dropbox

Save book to Google Drive