The molecular genetics of congenital heart disease: A review of recent developments

Current Opinion in Cardiology

Volumn 25, Issue 3, 2010, Pages 192-197

  Wolf, Michael ^a   Basson, Craig T ^b  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b NONE

Author keywords

Cardiac septation; Congenital heart disease; Conotruncal anomalies; Somatic mutations

Indexed keywords

B RAF KINASE; BONE MORPHOGENETIC PROTEIN 4; FIBROBLAST GROWTH FACTOR 8; JAGGED1; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; MYOSIN HEAVY CHAIN ALPHA; NOTCH1 RECEPTOR; PROTEIN TYROSINE PHOSPHATASE SHP 2; RAS PROTEIN; T BOX TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR ETS 1; TRANSCRIPTION FACTOR GATA; TRANSCRIPTION FACTOR GATA 4; TRANSCRIPTION FACTOR GATA 5; TRANSCRIPTION FACTOR GATA 6; TRANSCRIPTION FACTOR NKX2.5; TRANSCRIPTION FACTOR TBX5; VERSICAN;

CHROMOSOME 22Q; CHROMOSOME DELETION; CHROMOSOME DUPLICATION; CONGENITAL HEART DISEASE; COPY NUMBER VARIATION; EBSTEIN ANOMALY; FALLOT TETRALOGY; GENE EXPRESSION; GENE MUTATION; GENETIC ASSOCIATION; GREAT VESSELS TRANSPOSITION; HEART ATRIUM SEPTUM DEFECT; HEART RIGHT VENTRICLE DOUBLE OUTLET; HEART VENTRICLE SEPTUM DEFECT; HUMAN; HYPOPLASTIC LEFT HEART SYNDROME; JACOBSEN SYNDROME; LUNG VEIN DRAINAGE ANOMALY; MOLECULAR GENETICS; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION;

HEART DEFECTS, CONGENITAL; HEART SEPTAL DEFECTS; HUMANS; MOLECULAR BIOLOGY; MUTATION; TRANSCRIPTION FACTORS;

EID: 77952112456     PISSN: 02684705     EISSN: None     Source Type: Journal    
DOI: 10.1097/HCO.0b013e328337b4ce     Document Type: Review

References (54)

1. Pierpont ME, Basson CT, Benson DW, et al. 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. Circulation 2007;115:3015-3038.
2. American Heart Association. Heart Disease and Stroke Statistics - 2005 update. Dallas, Texas: American Heart Association.
3. Gatzoulis MA. Adult congenital heart disease: a cardiovascular area of growth in urgent need of additional resource allocation. Int J Cardiol 2004; 97 (Suppl 1) : 1-2.
4. Garg V. Insights into the genetic basis of congenital heart disease. Cell Mol Life Sci 2006;63:1141-1148.
5. Boughman JA, Neill CA, Ferencz C, Loffredo CA. The genetics of congenital heart disease. In: Ferencz C, Rubin JD, Loffredo CA, Magee CA, editors. Epidemiology of congenital heart disease: the Baltimore-Washington Infant Hear Study, 1981-1989. New York: Mount Kisco; 1993. pp. 123-164.
6. Reamon-Buettner SM, Spanel-Borowski K, Borlak J. Bridging the gap between anatomy and molecular genetics for an improved understanding of congenital heart disease. Ann Anat 2006;188:213-220.
7. Schott JJ, Benson DW, Basson CT, et al. Congenital heart disease caused by mutations in the transcription factor NKX2.5. Science 1998;281:108-111.
8. Benson DW, Silberback GM, Kavanaugh-McHugh A, et al. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest 1999;104:1567-1573.
9. Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with tetralogy of Fallot. Circulation 2001;104:2565-2568.
10. Garg V, Kathiriya IS, Barnes R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 2003;424:443-447.
11. Maitra M, Schluterman M, Nichols H, et al. Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol 2009;326:368-377. Interaction of Gata4 and Gata6 with Tbx5 affects late myocardial development, leading to heart failure and growth retardation through the Myh6 pathway.
12. Ching YH, Gosh TK, Cross SJ, et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet 2005;37:423-428.
13. Davis DL, Edwards AV, Juraszek AL, et al. A GATA-6 gene heart-regionspecific enhancer provides a novel means to mark and probe a discrete component of the mouse cardiac conduction system. Mech Dev 2001;108:105-119.
14. Singh MK, Li Y, Li S, et al. Gata4 and Gata5 cooperatively regulate cardiac myocyte proliferation in mice. J Biol Chem 2010;285:1765-1772. GATA5, not previously implicated in CHD, may play a crucial and somewhat redundant role as GATA4 in human CHD.
15. Tu CT, Yang TC, Tsai HJ. Nkx2.7 and Nkx2.5 function redundantly and are required for cardiac morphogenesis of zebrafish embryos. PLoS One 2009; 4: e4249. Nkx2.5 and Nkx2.7 seem to play critical yet somewhat redundant roles in cardiac looping in zebrafish.
16. Prall OW, Menon MK, Solloway MJ, et al. An Nkx2-5/Bmp2/SmadI negative feedback loop controls heart progenitor specification and proliferation. Cell 2007;128:947-959.
17. Srivasta D, Cserjesi P, Olson E. A subclass of bHLH proteins required for cardiac morphogenesis. Science 1995;270:1995-1999.
18. Riley P, Anson-Cartwright L, Cross JC. The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nat Genet 1998;18:271-285.
19. McFadden DG, Barbosa AC, Richardson JA, et al. The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependant manner. Development 2005;132:189-201.
20. Reamon-Buettner SM, Ciribilli Y, Traverso I, et al. A functional genetic study identifies HAND1 mutations in septation defects of the human heart. Hum Mol Genet 2009;18:3567-3578. HAND1, and its interaction with NKX2.5 and GATA4, is involved in cardiac septation defects.
21. Draus JM, Hauck MA, Goetsch M, et al. Investigation of somatic NKX2-5 mutations in congenital heart disease. J Med Genet 2009;46:115-122. Replicating initial studies of surgical CHD samples, the authors suggest that formalin fixation-induced DNA damage may have influence on detection of somatic mutations in early CHD samples.
22. Aanhaanen WTJ, Brons JF, Dominguez JN, et al. The Tbx2+ primary myo-cardium of the atrioventricular canal forms the atrioventricular node at the base of the left ventricle. Circ Res 2009;104:1267-1274. Tbx2 is shown to play a critical role in the formation of the atrioventricular canal, the left ventricular base, and the cardiac conduction system.
23. Wiese C, Grieskamp T, Airik R, et al. Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ Res 2009;104:388-397. Tbx3 and Tbx18 are shown to play critical roles in sinoatrial node formation.
24. Hirayama-Yamada K, Kamisago M, Akimoto K, et al. Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect. Am J Med Genet 2005;135:47-52.
25. Posch MG, Gramlich M, Sunde M, et al. A gain-of function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale, and cardiac valve defects. J Med Genet 2009. [Epub ahead of print] A novel mutation in TBX20 causes familial ASD through interaction with NKX2.5 and GATA4/5.
26. Lammer E, Chak J, Iovannisci D, et al. Chromosomal abnormalities among children born with conotruncal cardiac defects. Birth Defects Res 2009;85:30-35. Patients with TOF are more likely to have 22q11.2 deletions than those with TGA or DORV.
27. Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. JACC 1998;32:492-498.
28. Rauch R, Hofbeck M, Zweier C, et al. Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot. J Med Genet 2009. [Epub ahead of print] 22q11.2 is the most common genetic mutation in TOF. Mutations in TBX1, NKX2.5, and JAG1 have also been found in TOF patients. AVSD with TOF is highly associated with trisomy 21.
29. Edelmann L, Pandita RK, Morrow BE, et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum Mol Genet 1999;8:1157-1165.
30. Ou Z, Berg H, Yonath VB, et al. Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med 2008;4:267-277.
31. Ensenauer RE, Adeyinka A, Flynn HC, et al. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenic, and molecular analysis of thirteen patients. Hum Genet 2003;73:1027-1040.
32. Menten B, Maas N, Thienpont B, et al. Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports. J Med Genet 1998;43:625-633.
33. Zweier C, Sticht H, Aydin-Yaylagul I, et al. Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. Am J Hum Genet 2007;80:510-517.
34. Beckmann JS, Estivill X, Antonarakis SE. Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet 2007;8:639-646.
35. Greenway SC, Pereira AC, Lin JC, et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 2009;41:931-935. Up to 10% of sporadic TOF may be the result of CNVs. Seven CNVsare identified associated with nonsyndromic TOF, three of which encode genes previously known to cause CHD.
36. Grossfeld PD, Mattina T, Lai Z, et al. The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Gen 2004;15:51-61.
37. Phillips HM, Renforth GL, Spalluto C, et al. Narrowing the critical region within 11q24-qter for hypoplastic left heart and identification of a candidate gene, JAM3, expressed during cardiogenesis. Genomics 2002;79:475-478.
38. Ye M, Hamzeh R, Geddis A, et al. Deletion of JAM-C a candidate gene for heart defects in Jacobsen syndrome, results in a normal cardiac phenotype in mice. Am J Med Gen 2009; 149A: 1438-1443. JAM-C deletion in mice results in normal cardiac phenotype.
39. Ye M, Coldren C, Liang X, et al. Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal morphology in mice. Hum Mol Genet 2009;19:648-656. Deletion of Ets-1 in the cardiac critical region of 11q causes VSD and abnormal ventricular morphology in mice. Its expression in the endocardium may be responsible for normal myocardial morphogenesis.
40. Sato Y. Role of ETS family transcription factors in vascular development and angiogenesis. Cell Struct Funct 2001;26:19-24.
41. Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 1993;5:11-16.
42. Chen B, Bronson R, Klaman T, et al. Mice mutants for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet 2000;24:296-299.
43. Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-468.
44. Araki T, Mohi MG, Ismat FA, et al. Mouse model of Noonan syndrome reveals cell type and gene dosage dependant effects of Ptpn11 mutation. Nat Med 2004;10:849-857.
45. Araki T, Chan G, Newbigging S, et al. Noonan syndrome cardiac defects are caused by Ptpn11 acting in endocardium to enhance endocardial-mesenchymal transformation. PNAS 2009;106:4736-4741. Ptpn11 mutations result in expression of mutant Shp2, suggesting that valvular abnormalities of Noonan syndrome relate to defective endocardial-mesenchymal transformation in the endocardial cushion, in part modulated by Ras/Erk signaling.
46. Roberts A, Allanson J, Jadico SK, et al. The cardiofaciocutaneous syndrome. J Med Genet 2006;43:833-842.
47. Gripp KW, Lin AE, Nicholson L, et al. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardiofacio-cutaneous syndrome from Costello syndrome. Am J Med Genet 2007;143:1472-1480.
48. Dentici ML, Sarkozy A, Pantaleoni F, et al. Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. Euro J Med Genet 2009;17:733-740. CFCS patients with MEK1/MEK2 mutations have different cardiac phenotypes compared with patients with BRAF mutations.
49. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human JAGGED1 which encodes a ligand for NOTCH1. Nat Genet 1997;16:243-251.
50. Krantz ID, Smith R, Colliton RP, et al. JAGGED1 mutations in patients ascertained with isolated congenital heartdefects. Am J Med Genet 1999;84:56-60.
51. Garg V, Muth AN, Ransom JF. Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437:270-274.
52. Yang Ke, Doughman YQ, Karunamuni G, et al. Expression of active Notch1 in avian coronary development. Dev Dyn 2009;238:162-170. The NOTCH1 intracellular domain plays a role in epicardial cell transition and early coronary artery development.
53. High F, Jain R, Stoller J, et al. Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interaction during outflow tract development. J Clin Invest 2009;119:1986-1996. Inhibition of Notch1 or deletion of Jagged1 results in downregulated Fgf8 in secondary heart field derived myocardium, hypocellular endocardial cushions, and neural crest defects.
54. Park EJ, et al. Required, tissue specific roles for Fgf8 in outflow tract formation and remodeling. Development 2006;131:2419-2433.