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GENETICS OF FAMILIAL 
CONGENITAL HEART DISEASES 
Laxmi Ghimire, MD 
Clinical Fellow, Pediatric Cardiology 
UCSF Benioff Children’s Hospital 
San Francisco, CA
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.
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
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.
Multifactorial origin of CHD. 
Srivastava et al. Circulation. 2009;120:269-271
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
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
Molecular pathology of congenital heart disease 
Cell Mol Life Sci. 2014; 71: 1327–1352.
Genes associated with CHD 
CHD 
Genes encoding transcription 
factors 
Genes involved in cell 
signaling 
Genes encoding structural 
proteins 
Genes encoding epigenetic 
regulators
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
Danish registry with 1 763 591 persons born in Denmark 
Included patients from 1977 to 2005 
Total of 18 708 had CHD
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
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
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.
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
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
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
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
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

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Genetics of Congenital Heart Disease

  • 1. GENETICS OF FAMILIAL CONGENITAL HEART DISEASES Laxmi Ghimire, MD Clinical Fellow, Pediatric Cardiology UCSF Benioff Children’s Hospital San Francisco, CA
  • 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. 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. 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. Multifactorial origin of CHD. Srivastava et al. Circulation. 2009;120:269-271
  • 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. 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. Molecular pathology of congenital heart disease Cell Mol Life Sci. 2014; 71: 1327–1352.
  • 9. Genes associated with CHD CHD Genes encoding transcription factors Genes involved in cell signaling Genes encoding structural proteins Genes encoding epigenetic regulators
  • 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. Danish registry with 1 763 591 persons born in Denmark Included patients from 1977 to 2005 Total of 18 708 had CHD
  • 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. 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. 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. 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. 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. 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. 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. 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