Genetic aspects of Ebstein anomaly and related heart diseases

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Ebstein anomaly is a congenital heart disease, which is characterized by the presence of atrialized portion of the right ventricle, formed as a result of displacement of the tricuspid valve leaflets into the right ventricle and their partial adherence to the underlying myocardium. Atrialized portion in the right ventricle occupies the space between the fibrous annulus of the right atrioventricular orifice and the functional annulus of tricuspid valve, which represents a zone of closure of free (non-adherent to the underlying myocardium) edges of its leaflets. Ebstein anomaly is very rarely isolated, and can be combined with a number of heart diseases and be an integral part of hereditary syndromes. Currently, the role of genetic research in the investigation of the etiology of human diseases as well as understanding of the relationship between different diseases is increasing. The review presents literature data on the combination of Ebstein anomaly with other heart diseases (congenital heart diseases, Wolf-Parkinson-White syndrome, cardiomyopathies, including left ventricular noncompaction), inter alia, within the scope of hereditary syndromes (Noonan syndrome, 8p deletion syndrome, 18q deletion syndrome, 1p36 deletion syndrome, Pierre Robin syndrome). Genetic factors (gene and chromosomal mutations) lying at the core of Ebstein anomaly, as well as heart diseases combined with it, are highlighted. The analysis of published data suggests that Ebstein anomaly is a monogenic disease, and is characterized by allelic and locus genetic heterogeneity. The combination of Ebstein anomaly with other heart diseases is based on their genetic linkage.

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About the authors

Elena V. Penyaeva

A.N. Bakoulev National Medical Reresearch Center for Cardiovascular Surgery

Author for correspondence.
ORCID iD: 0000-0001-9692-2322
SPIN-code: 4958-8933
Scopus Author ID: 56185476600

Russian Federation, 135 Rublevskoe shosse, 121552, Moscow

MD, Senior Research Associate


  1. Attenhofer Jost CH, Connolly HM, Dearani JA, et al. Ebstein’s anomaly. Circulation. 2007;16;115(2):277–285. doi:
  2. Frescura C, Angelini A, Daliento L, Thiene G. Morphological aspects of Ebstein’s anomaly in adults. Thorac Cardiovasc Surg. 2000;48(4):203–208. doi:
  3. Khositseth A, Danielson GK, Dearani JA, et al. Supraventricular tachyarrhythmias in Ebstein anomaly: management and outcome. J Thorac Cardiovasc Surg. 2004;128(6):826–833. doi:
  4. Postma AV, van Engelen K, van de Meerakker J, et al. Mutations in the sarcomere gene MYH7 in Ebstein anomaly. Circ Cardiovasc Genet. 2011;4(1):43–50. doi:
  5. Laitenberger G, Donner B, Gebauer J, Hoehn T. D-transposition of the great arteries in a case of microduplication 22q11.2. Pediatr Cardiol. 2008;29(6):1104–1106. doi:
  6. de Agustín JA, Perez de Isla L, Zamorano JL. Ebstein anomaly and hypertrophic cardiomyopathy. Eur Heart J. 2008;29(20):2525. doi:
  7. Areias JC, Valente I. Congenital heart malformations associated with dilated cardiomyopathy. Int J Cardiol. 1987;17(1):83–88. doi:
  8. Benson DW, Silberbach GM, Kavanaugh-McHugh A, et al. Mutations in the cardiac transcription factor NKX 2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999;104(11):1567–1573. doi:
  9. Gioli-Pereira L, Pereira AC, Mesquita SM, et al. NKX 2.5 mutations in patients with non-syndromic congenital heart disease. Int J Cardiol. 2010;138(3):261–265. doi:
  10. de Lonlay-Debeney P, de Blois MC, Bonnet D, et al. Ebstein anomaly associated with rearragements of chromosomal region 11q. Am J Med Genet. 1998;80(2):157–159. doi:<157::AID-AJMG12>3.0.CO;2-U
  11. Бокерия Л.А., Шаталов К.В., Михайлова А.А. Особенности течения ближайшего послеоперационного периода у пациентов, страдающих синдромом Noonan, при выполнении хирургической коррекции врожденных пороков сердца // Детские болезни сердца и сосудов. — 2010. — № 1. — С. 33–40. [Bockeria LA, Shatalov KV, Mikhailova AA. Close postoperative course peculiarities in patients with Noonan syndrome after surgical correction of congenital heart defects. Detskie Bolezni Serdtsa i Sosudov. 2010;(1):33–40. (In Russ.)]
  12. Digilio MC, Bernardini L, Lepri F, et al. Ebstein Anomaly: Genetic Heterogenety and association with Microdeletions 1p36 and 8p23.1. Am J Med Genet A. 2011;155A(9):2196–2202. doi:
  13. Hutchinson R, Wilson M, Voullaire L. Distal 8p deletion (8p23.1→8pter): a common deletion? J Med Genet. 1992;29(6):407–411. doi:
  14. Van Trier DC, Feenstra I, Bot P, et al. Cardiac anomalies in individuals with the 18q deletion syndrome; report of a child with Ebstein anomaly and review of the literature. Eur J Med Genet. 2013;56(8):426–431. doi:
  15. Online Mendelian Inheritance in Man (OMIM) Ebstein anomaly 224700. Baltimore (MD): McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. [cited 02.12.2019]. Available from: http:
  16. Ouyang P, Saarel E, Bai Y, et al. A de novo mutation in NKX 2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death. Clin Chim Acta. 2011;412(1–2):170–175. doi:
  17. Harvey RP. NK-2 homeobox genes and heart development. Developmental Biology. 1996;178(2):203–216. doi:
  18. Tanaka M, Chen Z, Bartunkova S, et al. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development. 1999;126(6):1269–1280.
  19. Kasahara H, Lee B, Schott JJ, et al. Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease. J Clin Invest. 2000;106(2):299–308. doi:
  20. Никитина Л.В., Копылова Г.В., Щепкин Д.В., и др. Исследование молекулярных механизмов актин-миозинового взаимодействия в сердечной мышце // Успехи биологической химии. – 2015. – № 55.— С. 255–288. [Nikitina LV, Kopylova GV, Shchepkin DV, et al. The study of molecular mechanisms of actin-myosin interaction in the heart muscle. Uspekhi biologicheskoy khimii. 2015;55:255–288. (In Russ.)]
  21. Walsh R, Rutland C, Thomas R, Loughna S. Cardiomyopathy: a systematic review of disease-causing mutations in myosin heavy chain 7 and their phenotype manifestations. Cardiology. 2010;115(1):49–60. doi:
  22. Gaussin V, Morley GE, Cox L, et al. Alk3/Bmpr1a Receptor is required for Development of the Atrioventricular Canal into Valves and Annulus Fibrosus. Circ Res. 2005;97(3):219–226. doi:
  23. Breckpot J, Tranchevent LC, Thienpont B, et al. BMPR1A is candidate gene for congenital heart defects associated with therecurrent 10q22q23 deletion syndrome. Eur J Med Genet. 2012;55(1):12–16. doi:
  24. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors.2004;22(4):233–241. doi:
  25. Nohe A, Keating E, Knaus P, Petersen NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal. 2004;16(3):291–299. doi:
  26. Kratz CP, Franke L, Peters H, et al. Cancer Spectrum and Frequency among Children with Noonan, Costello and Cardio-facio-cutaneus Syndrome. Br J Cancer. 2015;112(8):1392–1397. doi:
  27. Digilio MC, Conti E, Sarkozy A, et al. Grouping of Multiple-Lentines/LEOPARD and Noonan Syndromes on the PTPN11 Gene. Am J Hum Genet. 2002;71(2):389–394. doi:
  28. Koch CA, Anderson D, Moran MF, et al. SH2 and SH3 domeins: Elements that control interactions of cytoplasmic signaling proteins. Science. 1991;252(5006):668–674. doi:
  29. Yang SH, Sharrocks AD, Whitmarsh AJ. MAP kinase signalling cascades and transcriptional regulation. Gene. 2013;513(1):1–13. doi:
  30. Фаллер Д.М., Шилдс Д. Молекулярная биология клетки. — М.: Бином, 2017. — 256 с. [Faller DM, Shilds D. Molekulyarnaya biologiya kletki. Moscow: Binom; 2017. 256 р. (in Russ.)]
  31. Newbern J, Zhong J, Wickramasinghe RS, et al. Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc Natl Acad Sci USA. 2008;105(44):17115–17120. doi:
  32. Balza RO Jr, Misra RP. Role of the serum response factor in regulating contractile apparatus gene expression and sarcomeric integrity in cardiomyocytes. J Biol Chem. 2006;281(10):6498–6510. doi:
  33. Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362(9393):1366–1373. doi:
  34. Xu YJ, Chen S, Zhang J, et al. Novel TBX1 loss-of-function mutation cause isolated conotruncal heart defects in Chinesepatients without 22q.11.2 deletion. BMC Med Genet. 2014;(15):78. doi:
  35. Hu T, Yamagishi H, Maeda J, McAnally J. Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors. Development. 2004;131(21):5491–5502. doi:
  36. Macatee TL, Hammond BP, Arenkiel BR, et al. Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development. Development. 2003;130(25):6361–6374. doi:
  37. Frank DU, Fotheringham LK, Brewer JA, et al. An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development. 2002;129:4591–4603.
  38. Alsan BH, Schultheiss TM. Regulation of avian cardiogenesis by Fgf8 signaling. Development. 2003;130(25):6361–6374.
  39. Shaikh TH, Kurahashi H, Saitta SC, et al. Chromosomee 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet. 2000;9(4):489–501. doi:
  40. Huang WY, Heng HH, Liew CC. Assignment of the human GATA4 gene to 8p23.1–p22 using fluoresence in situ hybridisation analysis. Cytogenet Cell Genet. 1996;72(2–3):217–218. doi:
  41. Durocher D, Charron F, Warren R, et al. The cardiac transcription factors Nkx2-5 and GATA4 are mutual cofactors. EMBO J. 1997;16(18):5687–5696. doi:
  42. 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):443–447. doi:
  43. Li X, Ho SN, Luna J, et al. Cloning and chromosomal localization of the human and murine genes for the T-cell transcription factors NFATc and NFATp. Cytogenet Cell Genet. 1995;68(3–4):185–191. doi:
  44. Müller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 2010;10(9):645–656. doi:
  45. de la Pompa JL, Timmerman LA, Takimoto H, et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature. 1998;392(6672):182–186. doi:
  46. Dupays L, Jarry-Guichard T, Mazurais D, et al. Dysregulation of connexins and inactivation of NFATc1 in the cardiovascular system of Nkx2-5 null mutants. J Mol Cell Cardiol. 2005;38(5):787–798. doi:
  47. Horsley V, Aliprantis AO, Polak L, et al. NFATc1 balances quiescence and proliferation of skin stem cells. Cell. 2008;132(2):299–310. doi:
  48. Han ZQ, Chen Y, Tang CZ, et al. Association between nuclear factor of activated T cells 1 gene mutation and simple congenital heart disease in children. Zhonghua Xin Xue Guan Bing Za Zhi. 2010;38(7):621–624.
  49. Battaglia A, Hoyme HE, Dallapiccola B, et al. Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation. Pediatrics. 2008;121(2):404–410. doi:
  50. Krief S, Faivre JF, Robert P, et al. Identification and characterization of cvHsp. A novel human small stress protein selectively expressed in cardiovascular and insulin-sensitive tissues. J Biol Chem. 1999;274(51):36592–36600. doi:
  51. Mymrikov EV, Daake M, Richter B, et al. The shaperone activity and substrate spectrum of human heat small shock proteins. J Biol Chem. 2017;292(2):672-684. doi:
  52. Ngo JT, Klisak I, Dubin RA, et al. Assignment of the alpha B crystallin gene to human chromosomу 11. Genomics. 1989;5(4):665–669.
  53. Venkatakrishnan CD, Tewari AK, Moldovan L, et al. Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27. Am J Phisiol Heart Circ Physiol. 2006;291(6):H2680-H2691. doi:
  54. Singh BN, Rao KS, Ramakrishna T, et al. Association of alpha B-crystallin, a small heat shock protein, with actin: role in modulating actin filament dynamics in vivo. J Mol Biol. 2007;366(3):756–767. doi:
  55. Golenhofen N, Ness W, Koob R, et al. Ischemia-induced phosphorilation and translocation of stress protein alpha B-crystallin to Z lines of myocardium. Am J Physiol. 1998;274(5 Pt 2):H1457–64.
  56. Егорова И.Ф., Пеняева Е.В., Бокерия Л.А. Изменения Z-дисков миофибрилл в кардиомиоцитах у больных с аномалией Эбштейна // Архив патологии. — 2015. — Т. 77. — № 6.— С. 3–8. [Egorova IF, Penyaeva EV, Bockeria LA. Altered Z-disks of myofibrils in the cardiomyocytes from patients with Ebstein’s anomaly. Arkhiv patologii. 2015;77(6):3–8. (In Russ.)] doi:
  57. Stark K, Esslinger UB, Reinhard W, et al. Genetic association study identifies HSPB7 as risc gene for idiopathic dilated cardiomyopathy. PLoS Genet. 2010;6(10):e1001167. doi:
  58. Inagaki N, Hayashi T, Arimura T, et al. Alpha B-crystallin mutation in dilated cardiomyopathy. Biochem Biophys Res Commun. 2006;342(2):379–386. doi:
  59. Бочков Н.П., Пузырев В.П., Смирнихина С.А. Клическая генетика. — М.: ГЕОТАР-Медиа, 2018. — 582 с. [Bochkov NP, Puzyrev VP, Smirnichina SA. Klicheskaya genetika. Moscow: GEOTAR-Media; 2018. 582 р. (In Russ.)]
  60. Курникова М.А., Блинникова Е.О., Мутовин Г.Р., и др. Современные представления о синдроме Элерса–Данлоса // Медицинская генетика. — 2004. — Т. 3. — № 4. — С. 10–17. [Kurnikova MA, Blinnikova EO, Mutovin GR, et al. Modern concept of Ehlers-Danlos syndrome. Meditsinskaya genetika. 2004;3(1):10–17. (In Russ.)].

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Picture. Diagram of molecular genetic signaling pathways responsible for the formation of AE and associated heart diseases

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