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  • Print publication year: 2020
  • Online publication date: October 2019

Chapter 13 - Structural Heart Disease: Genetic Influences

from Structural Heart Disease in the Fetus


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 a continued increase in 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 mean that genome-wide investigation is becoming more widely available in the 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 have for their patients.

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[1]van der Linde, D, Konings, EE, Slager, MA, Witsenburg, M, Helbing, WA, Takkenberg, JJ, Roos-Hesselink, JW. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011; 58: 2241–7.
[2]Ransom, J, Srivastava, D. The genetics of cardiac birth defects. Semin Cell Dev Biol. 2007; 18: 132–9.
[3]Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002; 39: 1890–900.
[4]Triedman, JK, Newburger, JW. Trends in Congenital Heart Disease, the next decade. Circulation. 2016; 133: 2716–33.
[5]Huang, JB, Liu, YL, Sun, PW, Lv, XD, Du, M, Fan, XM. Molecular mechanisms of congenital heart disease. Cardiovasc Pathol. 2010; 19: e183–93.
[6]Cai, GJ, Sun, XX, Zhang, L, Hong, Q. Association between maternal body mass index and congenital heart defects in offspring: a systematic review. Am J Obstet Gynecol. 2014; 211: 91117.
[7]Botto, LD, Panichello, JD, Brown, ML, Krikov, S, Feldkamp, ML, Lammer, E, et al. Congenital heart defects after maternal fever. Am J Obstet Gynecol. 2014; 210: e1–359. e11.
[8]Jenkins, KJ, Correa, A, Feinstein, JA, Botto, L, Britt, AE, Daniels, SR, 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: 29953014.
[9]Zhu, H, Kartiko, S, Finnell, RH. Importance of gene-environment interactions in the etiology of selected birth defects. Clin Genet. 2009; 75: 409–23.
[10]Nora, JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic-environmental interaction. Circulation. 1968; 38: 604–17.
[11]Schott, JJ, Benson, DW, Basson, CT, Pease, W, Silberbach, GM, Moak, JP, et al. Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science. 1998; 281: 108–11.
[12]Gebbia, M, Ferrero, GB, Pilia, G, Bassi, MT, Aylsworth, A, Penman-Splitt, M, et al. X-linked situs abnormalities result from mutations in ZIC3. Nat Genet. 1997; 17: 305–8.
[13]Gong, W, Gottlieb, S, Collins, J, Blescia, A, Dietz, H, Goldmuntz, E, et al. Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J Med Genet. 2001; 38: E45.
[14]Garg, V, Kathiriya, IS, Barnes, R, Schluterman, MK, King, IN, Butler, CA, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003; 424: 443–7.
[15]Pizzuti, A, Sarkozy, A, Newton, AL, Conti, E, Flex, E, Digilio, MC, et al. Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot. Hum Mutat. 2003; 22: 372–7.
[16]Sperling, S, Grimm, CH, Dunkel, I, Mebus, S, Sperling, HP, Ebner, A, et al. Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Hum Mutat. 2005; 26: 575–82.
[17]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: 1397–405.
[18]Wang, B, Yan, J, Peng, Z, Wang, J, Liu, S, Xie, X, Ma, X. Teratocarcinoma-derived growth factor 1 (TDGF1) sequence variants in patients with congenital heart defect. Int J Cardiol. 2011; 146: 225–7.
[19]Kosaki, R, Gebbia, M, Kosaki, K, Lewin, M, Bowers, P, Towbin, JA, Casey, B. Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet. 1999; 82: 70–6.
[20]Kosaki, K, Bassi, MT, Kosaki, R, Lewin, M, Belmont, J, Schauer, G, Casey, B. 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: 712–21.
[21]Bamford, RN, Roessler, E, Burdine, RD, Saplakoğlu, U, dela Cruz, J, Splitt, M, et al. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet. 2000; 26: 365–9.
[22]Garg, V, Muth, AN, Ransom, JF, Schluterman, MK, Barnes, R, King, IN, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005; 437: 270–4.
[23]Robinson, SW, Morris, CD, Goldmuntz, E, Reller, MD, Jones, MA, Steiner, RD, Maslen, CL. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet. 2003; 72: 1047–52.
[24]Karkera, JD, Lee, JS, Roessler, E, Banerjee-Basu, S, Ouspenskaia, MV, Mez, J, 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: 987–94.
[25]Mohapatra, B, Casey, B, Li, H, Ho-Dawson, T, Smith, L, Fernbach, SD, et al. Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet. 2009; 18: 861–71.
[26]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: 1323–9.
[27]Li, DY, Toland, AE, Boak, BB, Atkinson, DL, Ensing, GJ, Morris, CA, Keating, MT. Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet. 1997; 6: 1021–8.
[28]Muncke, N, Jung, C, Rüdiger, H, Ulmer, H, Roeth, R, Hubert, A, 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: 2843–50.
[29]Thienpont, B, Zhang, L, Postma, AV, Breckpot, J, Tranchevent, LC, Van Loo, P, et al. Haploinsufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet. 2010; 86: 839–49.
[30]Burn, J, Brennan, P, Little, J, Holloway, S, Coffey, R, Somerville, J, et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet. 1998; 351: 311–16.
[31]Grobman, W, Pergament, E. Isolated hypoplastic left heart syndrome in three siblings. Obstet Gynecol. 1996; 88: 673–5.
[32]Pease, WE, Nordenberg, A, Ladda, RL. Familial atrial septal defect with prolonged atrioventricular conduction. Circulation. 1976; 53: 759–62.
[33]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: 756–63.
[34]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: 942–5.
[35]Wessels, MW, Berger, RM, Frohn-Mulder, IM, Roos-Hesselink, JW, Hoogeboom, JJ, Mancini, GS, et al. Autosomal dominant inheritance of left ventricular outflow tract obstruction. Am J Med Genet A. 2005; 134A: 171–9.
[36]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: 673–7.
[37]van Egmond, H, Orye, E, Praet, M, Coppens, M, Devloo-Blancquaert, A. Hypoplastic left heart syndrome and 45X karyotype. Br Heart J. 1988; 60: 6971.
[38]van Bon, BW, Mefford, HC, Menten, B, Koolen, DA, Sharp, AJ, Nillesen, WM, 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: 511–23.
[39]Tartaglia, M, Mehler, EL, Goldberg, R, Zampino, G, Brunner, HG, Kremer, H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001; 29: 465–8.
[40]Zhao, Y, Ransom, JF, Li, A, Vedantham, V, von Drehle, M, Muth, AN, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129: 303–17.
[41]Hearn, T, Renforth, GL, Spalluto, C, Hanley, NA, Piper, K, Brickwood, S, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet. 2002; 31: 7983.
[42]Oda, T, Elkahloun, AG, Pike, BL, Okajima, K, Krantz, ID, Genin, A, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997; 16: 235–42.
[43]Newbury-Ecob, RA, Leanage, R, Raeburn, JA, Young, ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet. 1996; 33: 300–7.
[44]Brassington, AM, Sung, SS, Toydemir, RM, Le, T, Roeder, AD, Rutherford, AE, et al. Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet. 2003; 73: 7485.
[45]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: 1650–5.
[46]Carey, AH, Kelly, D, Halford, S, Wadey, R, Wilson, D, Goodship, J, et al. Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. Am J Hum Genet. 1992; 51: 964–70.
[47]Mefford, HC, Sharp, AJ, Baker, C, Itsara, A, Jiang, Z, Buysse, K, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008; 359: 1685–99.
[48]Hillman, K, DeVita, M, Bellomo, R, Chen, J. Meta-analysis for rapid response teams. Arch Intern Med. 2010; 170: 996–7; author reply 997.
[49]D’Amours, G, Kibar, Z, Mathonnet, G, Fetni, R, Tihy, F, Désilets, V, et al. Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clin Genet. 2011; 81: 128–41.
[50]Lazier, J, Fruitman, D, Lauzon, J, Bernier, F, Argiropoulos, B, Chernos, J, et al. Prenatal Array Comparative Genomic Hybridization in Fetuses With Structural Cardiac Anomalies. J Obstet Gynaecol Can. 2016; 38: 619–26.
[51]Lander, ES, Linton, LM, Birren, B, Nusbaum, C, Zody, MC, Baldwin, J, et al. Initial sequencing and analysis of the human genome. Nature. 2001; 409: 860921.
[52]Snyder, M, Du, J, Gerstein, M. Personal genome sequencing: current approaches and challenges. Genes Dev. 2010; 24: 423–31.