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Genetics of Congenital Heart Disease

This is presentation on the genetics of congenital heart diseases for any students interested in pediatric cardiology.

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Genetics of Congenital Heart Disease

  1. 1. GENETICS OF FAMILIAL CONGENITAL HEART DISEASES Laxmi Ghimire, MD Clinical Fellow, Pediatric Cardiology UCSF Benioff Children’s Hospital San Francisco, CA
  2. 2. Congenital Heart Diseases • Congenital heart disease is the leading cause of infant morbidity in the Western world • Nearly 1% of children have CHD, an additional 1% to 2% of the population harbor more subtle cardiac developmental anomalies. ~10X higher prenatal incidence. Hoffman. Pediatr Cardiol. 1995.16:155-65.
  3. 3. Congenital Heart Diseases • Most children born with CHD do not have other birth defects • CHD occurs in association with other anomalies or as part of an identified syndrome in 25 to 40% cases. ~ 1/3rd of children with a chromosomal abnormality will have CHD. • Aneuploidy, or abnormal chromosomal number, accounts for a significant proportion of CHD Bruneau. Nature. 2008 ;451:943-8
  4. 4. What causes CHD ? • The etiology of CHD is complex and is associated with both environmental and genetic causes. • Genetically, CHD is a very heterogeneous disease; 55 human disease genes have been identified so far and a lot more in mice.
  5. 5. Multifactorial origin of CHD. Srivastava et al. Circulation. 2009;120:269-271
  6. 6. Common syndromes resulting from Aneuploidy and microdeletions Syndrome Cardiac anomalies % with CHD Trisomy 13 ASD, VSD, PDA, HLHS 80% Trisomy 18 ASD, VSD, PDA, TOF, DORV, CoA, BAV 90-100% Trisomy 21 ASD, VSD, AVSD, TOF 40-50% Monosomy X(Turner Syndrome) CoA, BAV, AS, HLHS 25-35% 47, XXY(Klinefelter Syndrome) PDA, ASD, mitral valve prolapse 50% 22q11.2 deletion(DiGeorge Syndrome) IAA type B, aortic arch anomalies, truncus, TOF 75% 7q11.23 deletion(William- Beuren Syndrome) Supravalvar AS, PPS 50-85% Garg V. Current Cardiology Reviews, 2010, 6: 91-97
  7. 7. Common Syndromes Associated with CHD Resulting from Single Gene Defects Syndrome Cardiac anomalies Associated genes Noonan Syndrome PS with dysplastic pulmonary valve, AVSD, HCM, CoA PTPN11, KRAS, RAF1, SOS1 Costello Syndrome PS, HCM, cardiac conduction abnormalities HRAS LEOPARD Syndrome PS and cardiac conduction abnormalities PTPN11, RAF1 Alagille Syndrome PS, TOF, ASD, PPS JAG1, NOTCH2 Marfan Syndrome Aortic root dilation and dissection, MVP FBN1, TGFBR1, TGFBR2 Holt-Oram Syndrome ASD, VSD, AVSD, progressive AV conduction disease TBX5 Heterotaxy Syndrome DILV, DORV, d-TGA, AVSD ZIC3, CFC1 Char Syndrome PDA TFAP2b CHARGE Syndrome ASD, VSD, valve defects CHD7, SEMA3E Garg V. Current Cardiology Reviews, 2010, 6: 91-97
  8. 8. Molecular pathology of congenital heart disease Cell Mol Life Sci. 2014; 71: 1327–1352.
  9. 9. Genes associated with CHD CHD Genes encoding transcription factors Genes involved in cell signaling Genes encoding structural proteins Genes encoding epigenetic regulators
  10. 10. Non-Syndromic CHD associated with Single Gene Defects Cardiac anomalies Gene ASD, atrioventricular conduction delay, TOF, tricuspid valve abnormalities NKX2-5 ASD, VSD GATA4 ASD, hypertrophic cardiomyopathy MYH6 Cardiac septation defects associated with PHTN BMPR2 Endocardial cushion defects CRELD1, ALK2 BAV, early valve calcification NOTCH1 d-TGA PROSIT-240 Garg V. Current Cardiology Reviews, 2010, 6: 91-97
  11. 11. Danish registry with 1 763 591 persons born in Denmark Included patients from 1977 to 2005 Total of 18 708 had CHD
  12. 12. Risk of Recurrence of CHD by Family History of CHD Among First-Degree Relatives Heart defect in First-degree relative Same heart defect phenotype in cohort member No of CHD Relative risk 95% CI Heterotaxy 5 79.1 32.9-190 Conotruncal defect 27 11.7 8-17 Septal defects isolated 68 3.41 2.7-4.3 AVSD 8 24.3 12-49 LVOTO 13 12.9 7.5-22 RVOTO 12 48.6 27.5-86 Circulation. 2009;120:295-301
  13. 13. Relative Risk of Recurrence of Any CHD by Family History of CHDs Any type of CHD in Cohort Member Family Hx by Kinship type No. of CHD Relative risk 95% CI Twin, same sex 169 12.5 10.9-14.3 Twin, unlike sex 46 6.93 5.32-9.04 First-degree relative 549 3.21 2.96-3.49 Second-degree relative 443 1.78 1.09-2.91 Third-degree relative 387 1.10 0.81-1.48 Circulation. 2009;120:295-301
  14. 14. Familial congenital heart disease • Many congenital heart diseases run in families • With advances in genetics, we have been able to find the some of the genetic causes of familial congenital heart diseases • Knowledge of the familial contribution to congenital heart diseases (CHD) on an individual and population level is sparse Stalmans et al, Nat Med 2003: 173-82 Lambrechts et al. Nat Genet 2003; 34: 383-94.
  15. 15. Familial CHD: Role of VEGF • Vascular endothelial growth factor (VEGF) – plays critical role in the formation of the endocardial cushions during heart development in mouse model • Three SNPs in the promoter of VEGF (C2578A, G1154A, and C634G) shown to be a modifier of 22q11 deletion syndrome. Same haplotype was associated with lower VEGF levels in vivo. • In family based study: the low expression VEGF haplotype was transmitted more often to affected children suggesting that it may play a role in the development of isolated TOF Stalmans et al, Nat Med 2003: 173-82 Lambrechts et al. Nat Genet 2003; 34: 383-94. Lambrechts et al. J Med Genet 2005; 42: 519-22
  16. 16. Familial CHD: Role of VEGF • Newer data: VEGF do not play significant role in CHD • Genotyped 771 CHD cases, of whom 595 had Tetralogy of Fallot (TOF), and carried out case-control analyses using haplotype-tagging SNPs in VEGF. • Common or rare genetic variation in VEGF does not significantly predisposes to the risk of TOF Griffin et al. PLoS One. 2009;4:e4978
  17. 17. MTHFR and CHD • Initial studies showed strong association between MTHFR and CHD • Data is all over the place • A recent very large study: analyzed primary genotyping data on 5814 CHD cases and 10 056 controls, together with meta-analysis of a further 1883 cases and 3103 controls • They found no significant effect of MTHFR C677T genotype on CHD risk. Mamasoula et al. Circ Cardiovasc Genet. 2013. 6:347-53
  18. 18. Familial CHD and GATA4 • GATA- family of transcription factors and upstream regulator of genes expressed during embryogenesis and cardiac morphogenesis • GATA4 and familial TOF • Three novel heterozygous mutations of GATA4: p.A9P, p.L51V, and p.N285S, were identified in three families with TOF. • In each family, the mutant allele was present in all the affected family members but absent in unaffected relatives HumMutat 34:1662–1671, 2013
  19. 19. Familial congenital heart disease • A family history of any heart defect among first-degree relatives accounts for ~2-5% of the heart defect cases in the population. • The same heart defect phenotype show strong familial clustering, with relative risks of recurrence of 3-fold to 80-fold in first-degree relatives. • Few candidate genes have been systematically investigated for any possible contribution of common variants to disease risk. • There is limited data, if any, on identification of culprit genes/SNPs through whole genome sequencing on familial congenital heart diseases. Circulation. 2009;120:295-301