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The Etiology of Human Congenital Heart Defects

The Etiology of Human Congenital Heart Defects. Literature Seminar Feb 19 2009 Bernard Thienpont. Congenital Heart Defect. structural anomaly of the heart, present at birth not necessarily manifest in the neonatal period can remain benign throughout life.

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The Etiology of Human Congenital Heart Defects

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  1. The Etiology of Human Congenital Heart Defects Literature Seminar Feb 19 2009 Bernard Thienpont

  2. Congenital Heart Defect • structural anomaly of the heart, present at birth • not necessarily manifest in the neonatal period • can remain benign throughout life

  3. Congenital Heart Disease Congenital heart defect (Congenital) Cardiomyopathy (Congenital) Rhythm Disturbance

  4. Congenital Heart Disease A = Secondary to B Congenital heart defect (Congenital) Cardiomyopathy Congenital Rhythm Disturbance

  5. Congenital Heart Disease A & B share an underlying cause (same gene independently associated with both) Congenital heart defect NKX2.5 ACTC (Congenital) Cardiomyopathy Congenital Rhythm Disturbance

  6. Heart formation 1. heart field specification

  7. van Wijk, Moorman & van den Hoff , 2006

  8. Heart formation 2. Heart tube formation

  9. Moorman & VandenBerg, 2009

  10. Concomitant neural crest induction

  11. Heart formation 3. Heart chamber formation

  12. Moorman & VandenBerg, 2009

  13. Black, 2007

  14. http://pie.med.utoronto.ca/HTBG/HTBG_content/HTBG_heartEmbryologyApp.htmlhttp://pie.med.utoronto.ca/HTBG/HTBG_content/HTBG_heartEmbryologyApp.html

  15. Different chamber identities

  16. Heart formation 4. Outflow tract septation

  17. Black, 2007 Semin Cell Dev Biol. 2007 February; 18(1): 101–110

  18. Black, 2007 Semin Cell Dev Biol. 2007 February; 18(1): 101–110

  19. Heart formation 5. Ventricular septation

  20. Cai et al, nature 2008

  21. Heart formation 5. Atrial septation

  22. CHDs: Classifications • Why? Many CHDs are complex Different patients can have similar CHDs to a varying extent

  23. CHDs: Classifications Anatomical: • Group CHDs that affect the same cardiac structure e.g. AEPC Abnormalities of : • Position and connection of heart • Tetralogy of Fallot and variants • Great veins • atriums and atrial septum • AV valves and AV septal defect • Ventricles and ventricular septum • VA valves and great arteries • Coronary arteries, arterial duct and pericardium Embryological: • Group CHDs that are caused by the same embryological problem e.g. Boughman et al., AJMG 1987 Abnormalities because of • Cell migration problems • Flow lesions • Cell death • Extracellular matrix • Targeted growth defects • other

  24. e.g. VSD Anatomical: Group CHDs that affect the same cardiac structure e.g. AEPC Abnormalities of : • Position and connection of heart • Tetralogy of Fallot and variants • Great veins • atriums and atrial septum • AV valves and AV septal defect • Ventricles and ventricular septum • VA valves and great arteries • Coronary arteries, arterial duct and pericardium Embryological: Group CHDs that are caused by the same embryological problem e.g. Boughman et al., AJMG 1987 Abnormalities because of • Cell migration problems VSD-I • Flow lesions VSD-II • Cell death VSD-III • Extracellular matrix VSD-IV • Targeted growth defects • other

  25. Frequency of CHDs Hoffman & Kaplan (2002)

  26. Clinical classification Isolated vs syndromic CHDs ? Second major malformation ? Dysmorphism (3 or more minor malformations) Δ etiology: Mostly multifactorial vs single (genetic) cause

  27. Syndromic vs isolated CHDs Greenwood (1975) & Pradatet al. (2003)

  28. Causes of CHDs • Environmental or genetic?

  29. Environmental causes • Teratogens • Alcohol • α-epileptica • PKU

  30. Environmental causes • Teratogens • PKU • Viral infections?

  31. Environmental causes • Teratogens • PKU • Viral infections • Pregestational diabetes  Major CHDs: TGA PTA AVSD

  32. Environmental causes • Teratogens • PKU • Viral infections • Pregestational diabetes • Twinning

  33. Twinning ~ chorionic & amnioticstructures: DC/DA  1%

  34. Twinning ~ chorionic & amnioticstructures: DC/DA  1% MC/DA  5-7% (concordance = 25-50%)  TTT: 8% vs 3.4%

  35. Twinning ~ chorionic & amnioticstructures: DC/DA  1% MC/DA  5-7% (concordance = 25-50%) MC/MA  28% (often right atrial isomerism)

  36. Twin studies Problematic MZ : 25-50% concordance DZ : 13% concordance discordance? • Postzygotic mutations • Epigenetic Δ (e.g. X inactivation) • Stochastic factors Catastrophic Chance • …

  37. Genetic causes Population risk = 0.8% Relative risk: x1.3 x5 x4.3

  38. Genetic causes Familialaggregation Excluding BAV

  39. Genetic causes CHD Frequency in parents of CHD children

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