Skip to main content
SpringerLink
Log in

Familial recurrence of congenital heart disease: an overview and review of the literature

  • Review
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Familial recurrence is one of the classic patterns for the clinical presentation of congenital heart disease (CHD). In recent years, many groups studied empiric recurrence risk in these heart defects, and the aim of this review was to analyse the patterns of inheritance detected in different types of CHD, including atrioventricular canal defect, tetralogy of Fallot, transposition of the great arteries, left-sided obstructions and atrial septal defect. These studies may influence clinical practise guidelines through accurate genetic counselling, but also, they may have important implications in the knowledge of genetic and pathogenetic mechanisms of CHD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CHD:

Congenital heart disease

AVCD:

Atrioventricular canal defect

TOF:

Tetralogy of Fallot

TGA:

Transposition of the great arteries

CCTGA:

Congenitally correct transposition of the great arteries

ASD:

Atrial septal defect

References

  1. Bamford RN, Roessler E, Burdine RD, Saplakogu U, dela Cruz J, Splitt M, Towbin J, Bowers P, Marino B, Schier AF, Shen MM, Muenke M, Casey B (2000) Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human human left-right laterality defects. Nat Genet 26:365–369

    Article  PubMed  CAS  Google Scholar 

  2. Benson DW, Sharkey A, Fatkin D, Lang P, Basson CT, McDonough B, Strauss AW, Seidman JG, Seidman CE (1998) Reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects. Circulation 97:2043–2048

    PubMed  CAS  Google Scholar 

  3. Burn J, Brennan P, Little J, Holloway S, Coffey R, Somerville J, Dennis, Allan L, Arnold R, Deanfield JE, Godman M, Houston A, Keeton B, Oakley C, Scott O, Silove E, Wilkinson J, Pembrey M, Hunter AS (1998) Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 351:311–316

    Article  PubMed  CAS  Google Scholar 

  4. Ching YH, Ghosh TK, Cross SJ, Packham EA, Honeyman L, Loughna S, Robinson TE, Dearlove AM, Ribas G, Bonser AJ, Thomas NR, Scotter AJ, Caves LS, Tyrrell GP, Newbury-Ecob RA, Munnich A, Bonnet D, Brook JD (2005) Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet.37:423–428

    Article  PubMed  CAS  Google Scholar 

  5. Cousineau AJ, Lauer RM, Pierpont ME, Burns TL, Ardiger RH, Patil SR, Sheffield VC (1994) Linkage analysisof autosomal dominant atrioventricular canal defects: exclusion of chromosome 21. Hum Genet 93:103–108

    Article  PubMed  CAS  Google Scholar 

  6. Digilio MC, Marino B, Cicini MP, Giannotti A, Formigari R, Dallapiccola B (1993) Risk of congenital heart defects in relatives of patients with atrioventricular canal. Am J Dis Child 147:1295–1297

    PubMed  CAS  Google Scholar 

  7. Digilio MC, Marino B, Giannotti A, Dallapiccola B (1994) Familial atrioventricular septal defect: possible genetic mechanism. Br Heart J 72:301

    PubMed  CAS  Google Scholar 

  8. Digilio MC, Marino B, Toscano A, Giannotti A, Dallapiccola B (1999) Atrioventricular canal defect without Down syndrome: A heterogeneous malformation. Am J Med Genet 85:140–146

    Article  PubMed  CAS  Google Scholar 

  9. Digilio MC, Marino B, Giannotti A, Toscano A, Dallapiccola B (1997) Recurrence risk figures for isolated tetralogy of Fallot after screening for 22q11 microdeletion. J Med Genet 34:188–190

    Article  PubMed  CAS  Google Scholar 

  10. Digilio MC, Casey B, Toscano A, Calabrò R, Pacileo G, Marasini M, Banaudi E, Giannotti A, Dallapiccola B, Marino B (2001) Complete transposition of the great arteries: patterns of congenital heart disease in familial precurrence. Circulation 104:2809–2814

    PubMed  CAS  Google Scholar 

  11. Digilio MC, Marino B, Canepa SA, Borzaga U, Giannotti A, Dallapiccola B (1998) Congenital heart defect in sibs with discordant karyotypes. Am J Med Genet 80:169–172

    Article  PubMed  CAS  Google Scholar 

  12. Digilio MC, Marino B, Capolino R, Angioni A, Sarkozy A, Roberti MC, Conti E, De Zorzi A, Dallapiccola B (2005) Familial recurrence of nonsyndromic congenital heart defects in first degree relatives of patients with deletion 22q11.2. Am J Med Genet A 134:158–164

    PubMed  Google Scholar 

  13. Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC (2001) Familial tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Molec Genet 10:163–169

    Article  PubMed  CAS  Google Scholar 

  14. Elliott DA, Kirk EP, Yeoh T, Chandar S, McKenzie F, Taylor P, Grossfeld P, Fatkin D, Jones O, Hayes P, Feneley M, Harvey RP (2003) Cardiac homeobox gene NKX2-5 mutations and congenital heart disease. Association with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol 41:2072–2076

    Article  PubMed  CAS  Google Scholar 

  15. Emanuel R, Nichols J, Anders JM, Moores EC, Somerville J (1968) Atrioventricular defects: a study of 92 families. Br Heart J 30:645–653

    PubMed  CAS  Google Scholar 

  16. Emanuel R, Somerville J, Inns A, Withers R (1983) Evidence of congenital heart disease in the offspring of parents with atrioventricular defects. Br Heart J 49:144–147

    PubMed  CAS  Google Scholar 

  17. Ferencz C, Rubin JD, Loffredo CA, Magee CA (1993) Epidemiology of congenital heart disease: the Baltimore-Washington Infant Study, 1981–1989. Futura Publishing Company, New York

    Google Scholar 

  18. Fuhrmann W (1968) A family study in transposition of the great vessels and in tricuspid atresia. Humangenetik 6:148–157

    Article  PubMed  CAS  Google Scholar 

  19. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447

    Article  PubMed  CAS  Google Scholar 

  20. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D (2005) Mutations in Notch1 cause aortic valve disease. Nature 437:270–274

    Article  PubMed  CAS  Google Scholar 

  21. Gennarelli M, Novelli G, Digilio MC, Giannotti A, Marino B, Dallapiccola B (1994) Exclusion of linkage with chromosome 21 in families with recurrence of non-Down’s atrioventricular canal. Hum Genet 94:708–710

    Article  PubMed  CAS  Google Scholar 

  22. Goldmuntz E, Geiger E, Benson DW (2001) NKX2.5 mutations in patients with tetralogy of Fallot. Circulation 104:2565–2568

    PubMed  CAS  Google Scholar 

  23. Guenthard J, Buehler E, Jaeggi E, Wyler F (1994) Possible genes for left heart formation on 11q23.3. Ann Genet 37:143–146

    PubMed  CAS  Google Scholar 

  24. Kumar A, Williams CA, Victorica BE (1994) Familial atrioventricular septal defect: possible genetic mechanisms. Br Heart J 71:79–81

    PubMed  CAS  Google Scholar 

  25. Loffredo CA, Chokkalingam A, Sill AM, Boughman JA, Clark EB, Scheel J, Brenner JI (2004) Prevalence of congenital cardiovascular malformations among relatives of infants with hypoplastic left heart, coarctation of the aorta, and d-transposition of the great arteries. Am J Med Genet A 124:225–230

    Article  PubMed  Google Scholar 

  26. Marino B, Vairo U, Corno A, Nava S, Guccione P, Calabrò R, Marcelletti C (1990) Atrioventricular canal in Down syndrome. Prevalence of associated cardiac malformations compared with patients without Down syndrome. Am J Dis Child 144:1120–1122

    PubMed  CAS  Google Scholar 

  27. Miller ME, Smith DW (1979) Conotruncal malformation complex: examples of possible monogenic inheritance. Pediarics 63:890–893

    CAS  Google Scholar 

  28. McBride KL, Pignatelli R, Lewin M, Ho T, Fernbach S, Menesses A, Lam W, Leal SM, Kaplan N, Schliekelman, Towbin JA, Belmont JW (2005) Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability. Am J Med Genet A 234:180–186

    Google Scholar 

  29. Nomura M, Li E (1998) Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393:786–790

    Article  PubMed  CAS  Google Scholar 

  30. Nora JJ (1968) Multifactorial inheritance hypothesis for the etiology of congenital heart disease. The genetic environmental interaction. Circulation 38:604–617

    PubMed  CAS  Google Scholar 

  31. Nora JJ, Berg K, Nora AH (1991) Cardiovascular diseases. Genetics, epidemiology and prevention. In: Oxford University Press Inc., New York, pp 53–80

    Google Scholar 

  32. Nora JJ, Nora AH (1988) Update on counselling the family with a first-degree relative with a congenital heart defect. Am J Med Genet 29:137–142

    Article  PubMed  CAS  Google Scholar 

  33. O’Nuallain S, Hall JG, Stamm SJ (1977) Autosomal dominant inheritance of endocardial cushion defect. Birth Defects: original Article Series XIII:143–147

    Google Scholar 

  34. Pexieder T, Blanc O, Pelouch V, Ostadalova I, Milerova M, Ostadal B (1995) Late fetal development of retinoic acid-induced transposition of the great arteries: Morphology, physiology and biochemistry. In: Clark EB, Markwald RR, Takao A, (eds) Developmental mechanism of heart disease. Futura Publishing Company, New York pp 297–307

    Google Scholar 

  35. Piacentini G, Digilio MC, Capolino R, De Zorzi A, Toscano A, Sarkozy A, D’Agostino R, Marasini M, Russo MG, Dallapiccola B, Marino B (2005) Familial recurrence of heart defects in subjects with congenitally corrected transposition of the great arteries. Am J Med Genet A 137:176–180

    PubMed  Google Scholar 

  36. Pizzuti A, Sarkozy A, Newton AL, Conti E, Flex E, Digilio MC, Amati F, Gianni D, Tandoi C, Marino B, Crossley M, Dallapiccola B (2003) Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot. Hum Mut 22:372–377

    Article  PubMed  CAS  Google Scholar 

  37. Robinson SW, Morris CD, Goldmuntz E, Reller MD, Jones MA, Steiner RD, Maslen CL (2003) Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 72:1047–1052

    Article  PubMed  CAS  Google Scholar 

  38. Sanchez-Cascos A (1978) The recurrence risk in congenital heart disease. Eur J Cardiol 7:197–210

    PubMed  CAS  Google Scholar 

  39. Sarkozy A, Conti E, Neri C, D’Agostino R, Digilio MC, Esposito G, Toscano A, Marino B, Pizzuti A, Dallapiccola B (2005) Spectrum of atrial septal defects associated with mutations of NKX2.5 and GATA4 transcription factors. J Med Genet 42:e16

    Article  PubMed  CAS  Google Scholar 

  40. Sarkozy A, Esposito G, Conti E, Digilio MC, Marino B, Calabrò R, Pizzuti A, Dallapiccola B (2005) CRELD 1 and GATA4 gene analysis in patients with nonsyndromic atrioventricular canal defects. Am J Med Genet 139:236–238

    Article  PubMed  Google Scholar 

  41. Sarkozy A, Lepri F, Marino B, Pizzuti A, Digilio MC, Dallapiccola B (2006) Additional evidence that PTPN11 mutations play only a minor role in the pathogenesis of non-syndromic atrioventricular canal defect. Am J Med Genet 140(A):1970–1972

    Article  PubMed  Google Scholar 

  42. Schott J-J, Benson DW, Basson CT, Pease W, Silberbach, GM, Moak JP, Maron BJ, Seidman CE, Seidman JG (1998) Congenital heart disease caused by mutations in the transcription factor NKX2.5. Science 281:108–111

    Article  PubMed  CAS  Google Scholar 

  43. Sheffield VC, Pierpont ME, Nishimura D, Beck JS, Burns TL, Berg MA, Stone EM, Patil SR, Lauer RM (1997) Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis. Hum Mol Genet 6:117–121

    Article  PubMed  CAS  Google Scholar 

  44. Tennant SN, Hammon JW, Bender HW, Graham TP, Primm RK (1984) Familial clustering of atrioventricular canal defects. Am Heart J 108:175–177

    Article  PubMed  CAS  Google Scholar 

  45. Weismann CG, Hager A, Kaemmerer H, Maslen CL, Morris CD, Schranz D, Kreuder J, Gelb BD (2005) PTPN11 mutations play a minor role in isolated congenital heart disease. Am J Med Genet 135:146–151

    Article  Google Scholar 

  46. Wessels MW, Berger RMF, Frohn-Mulder IME, Roos-Hesselink JWR, Hoogeboom JJM, Mancini GS, Bartelings MM, de Krijger R, Wladimiroff JW, Niermeijer MF, Grossfeld P, Willems PJ (2005) Autosomal dominant inheritance of left ventricular outflow tract obstruction. Am J Med Genet 134:171–179

    Article  Google Scholar 

  47. Whittemore R, Hobbins JC, Engle MA (1982) Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease. Am J Cardiol 50:641–651

    Article  PubMed  CAS  Google Scholar 

  48. Wilson L, Curtis A, Korenberg JR, Schipper RD, Allan L, Chenevix-Trench G, Stephenson A, Goodship J, Burn J (1993) A large, dominant pedigree of atrioventricular septal defect (AVSD): Exclusion from the Down syndrome critical region on chromosome 21. Am J Hum Genet 53:1262–1268

    PubMed  CAS  Google Scholar 

  49. Wulfsberg EA, Zintz EJ, Moore JW (1991) The inheritance of conotruncal malformations: a review and report of two siblings with tetralogy of Fallot and pulmonary atresia. Clin Genet 40:12–16

    Article  PubMed  CAS  Google Scholar 

  50. Zatika M, Priestley M, Ladusans EJ, fryer AE, Mason J, Latif F, Maher ER (2005) Analysis of CRELD1 as a candidate 3p25 atrioventricular septal defect locus (AVSD2). Clin Genet 67:526–528

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Cardiology, Department of Pediatrics, University La Sapienza, Rome, Italy

    Giulio Calcagni & Bruno Marino

  2. Division of Medical Genetics, Bambino Gesù Hospital, Rome, Italy

    M. Cristina Digilio

  3. Department of Experimental Medicine and Pathology, University La Sapienza and CSS-Mendel Institute, Rome, Italy

    Anna Sarkozy & Bruno Dallapiccola

  4. Pediatric Cardiology, University “La Sapienza”, Viale Regina Elena 324, 00161, Rome, Italy

    Bruno Marino

Authors
  1. Giulio Calcagni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Cristina Digilio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Sarkozy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruno Dallapiccola
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruno Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruno Marino.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calcagni, G., Digilio, M.C., Sarkozy, A. et al. Familial recurrence of congenital heart disease: an overview and review of the literature. Eur J Pediatr 166, 111–116 (2007). https://doi.org/10.1007/s00431-006-0295-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-006-0295-9

Keywords

Search

Navigation