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

CH

D

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