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

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