The Etiology of Human Congenital Heart Defects Literature Seminar Feb 19 2009 Bernard Thienpont.
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Transcript of The Etiology of Human Congenital Heart Defects Literature Seminar Feb 19 2009 Bernard Thienpont.
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
Congenital Heart Disease
Congenital heart defect
(Congenital) Cardiomyopathy (Congenital) Rhythm Disturbance
Congenital Heart Disease
Congenital heart defect
(Congenital) Cardiomyopathy Congenital Rhythm Disturbance
A = Secondary to B
Congenital Heart Disease
Congenital heart defect
(Congenital) Cardiomyopathy Congenital Rhythm Disturbance
A & B share an underlying cause
(same gene independently associated with both)
NKX2.5ACTC
Heart formation
1. heart field specification
van Wijk, Moorman & van den Hoff , 2006
Heart formation
2. Heart tube formation
Moorman & VandenBerg, 2009
Concomitant neural crest induction
Heart formation
3. Heart chamber formation
Moorman & VandenBerg, 2009
Black, 2007
http://pie.med.utoronto.ca/HTBG/HTBG_content/HTBG_heartEmbryologyApp.html
Different chamber identities
Heart formation
4. Outflow tract septation
Black, 2007
Semin Cell Dev Biol. 2007 February; 18(1): 101–110
Black, 2007
Semin Cell Dev Biol. 2007 February; 18(1): 101–110
Heart formation
5. Ventricular septation
Cai et al, nature 2008
Heart formation
5. Atrial septation
CHDs: Classifications
• Why?Many CHDs are complexDifferent patients can have similar CHDs to a
varying extent
CHDs: ClassificationsAnatomical: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
e.g. VSDAnatomical: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
Frequency of CHDsVSD
ASD
PS
ToF
Coarc
AoS
AVSD
TGA
HLH
DORV
Pulmonary atresia
Ebstein
Single ventricle
TA
TAPVC
Tricuspid valve atresia
Hoffman & Kaplan (2002)
Clinical classification
Isolated vs syndromic CHDs? Second major malformation? Dysmorphism (3 or more minor malformations)
Δ etiology:Mostly multifactorial vs single (genetic) cause
Syndromic vs isolated CHDs
dTGA AS
Ebstein PA AS SV TA
PDAASD
0%10%20%30%40%50%60%70%80%90%
100%
Greenwood (1975) & Pradat et al. (2003)
Causes of CHDs
• Environmental or genetic?
Environmental causes
• Teratogens – Alcohol– α-epileptica
• PKU
Environmental causes
• Teratogens • PKU• Viral infections?
1 2 3 4 5 6 7 8 9 10 11 120.50.60.70.80.9
11.11.21.31.41.5
Environmental causes
• Teratogens• PKU• Viral infections• Pregestational diabetes
Diabetic Non-diabeticCVM 22 1417
Normal 587 1905923.61% 0.74% Major CHDs:TGAPTAAVSD
Environmental causes
• Teratogens• PKU• Viral infections• Pregestational diabetes• Twinning
Twinning
~ chorionic & amniotic structures:DC/DA 1%
Twinning
~ chorionic & amniotic structures:DC/DA 1%MC/DA 5-7% (concordance = 25-50%)
TTT: 8% vs 3.4%
Twinning
~ chorionic & amniotic structures:DC/DA 1%MC/DA 5-7% (concordance = 25-50%)
MC/MA 28% (often right atrial isomerism)
Twin studies
ProblematicMZ : 25-50% concordanceDZ : 13% concordance
discordance?– Postzygotic mutations– Epigenetic Δ (e.g. X inactivation)– Stochastic factors
Catastrophic Chance
– …
Genetic causes
x1.3
x4.3x5
Population risk = 0.8% Relative risk:
Genetic causes
Familial aggregationExcluding BAV
AoS ASD AVSD Coarc HLH PS ToF TGA TA VSD CHD0%
2%
4%
6%
8%
10%
12% SibsParentsChildren
Genetic causes
CHD Frequency in parents of CHD children
AoS ASD AVSD Coarc HLH PS ToF TGA TA VSD CHD0%
1%
2%
3%
4%
5%
6%
7%
8%
Parents
mothers
fathers
Genetic causes
CHD frequency in children of CHD parents
AoS ASD AVSD Coarc HLH PS ToF TGA TA VSD CHD0%
2%
4%
6%
8%
10%
12%
Childrenmother is probandfather is proband
Genetic causes
Familial aggregation: caveats– Ascertainment bias– Mailing questionairs– Inclusion criteria– Classification differences
Genetic causes
Increased transmission of CHD via mother • > Male susceptibility• Mitochondrial?• Imprinting
Classification of genetic causes
• genetic lesionsmall mutations ↔ chromosomal aberrations
• inheritance patternAD, AR, XL, other
• pathogenic mechanism of the mutationLoss-of-function, gain-of-function, dominant-negative
• number of loci involved:monogenic, oligogenic, polygenic
genetic lesion
small mutations ↔ chromosomal aberrations• Based on detection technique• Distinction = blurring
genetic lesion
small mutations • Syndromic / isolated• De novo / familial• Monogenic
• Frequent SNPs
– ELN– CREBBP– NKX2-5
chromosomal aberrations• Syndromic (± 55% of sCHD)• de novo• Often contiguous gene
syndromes• ID = diagnosis
– AVSD in T21– ASD, VSD, PS in 4p-– aortic abnormalities in 45,X
Inheritance pattern: AD
• 37/51 genes that are associated with CHDs– 22/37 loss of function
• signaling molecules• transcription factors• Transcription modulators
– Dominant-negative• Alagille (JAGGED1)• Structural proteins (MYH6, MYH11, ACTC1, …)
– Gain-of-function• Noonan/CFC/Costello• Rarely: TBX5, TBX1
Inheritance pattern: XL
• 6/51: XL• All but ZIC3: syndromic• Turner (45,X)
40%: CVM (L-OFT abn: Coarc, AS, HLH)
Etiology?Pre-X-inactivation? UnlikelyPAR?10% of genes escape X-inactivation
Inheritance pattern: XL
male preponderance:
ASdTGA
HLHCoarc
DORV
TAPVR PA ToFASD
AVSD0%
10%20%30%40%50%60%70%80%90%
100%
femalemale
The number of loci
rela
tive
risk
& e
ffect
size
population frequency
monogenic
oligogenic
polygenic
Monogenic
Most mutations causing iCHDs high penetrance
ascertainment bias !!most genes: linkage studies (necessarily high penetrance)
Monogenic
Variable penetrance & expressivityDue to
Type of mutation (eg TBX5)Modifiers eg VEGF polymorphisms in del22q11 + CHD
CRELD1 mutations in T21 + AVSD
Monogenic
Variable penetrance & expressivityYET:Typical CHDs
eg AVSD in T21conotruncul malformations in del22q11Familial CHDs: high concordance
Oligogenic
• No segregation of mutation with phenotype• Rare & unique mutations• Gene ID: candidate gene approach• Sequencing patients and normal controls• Functional studies
Oligogenice.g. FOXH1, GDF1, CFC1 and TDGF1:27/375 patients carry a mutation vs 0/125 control
Oligogenic
Functional studies
Polygenic
• SNPs that predispose to CHDs• Different constellations:
– Polymorphism in cis on same allele • eg T21
– Polymorphism in cis on other allele • eg del22q11: no SNPs in TBX1 are associated with CHDs
(Rauch 2004)
– Polymorphism in trans• VEGF in 22q11
Polygenic
• Low effect size• likely environmental contribution
Multifactorial (genes + environment)e.g.
SNP in NNMT risk does not increase significantlylow Nicotamide intake risk does not increase significantly
SNP in NNMT + low Nicotamide intake significantly increased risk
Gene identification: Challenges
• Large cohort of different types of CHD• Sequence patients and controls (1000 genomes)
• Include CNV analysis• Functional studies to prove pathogenic nature• Link between CHD and defect in heart
formation is often unclear