Transcript CHD

Genetics of
Congenital Heart Disease
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: A705, Research Building
2013/03
Required Reading
Thompson &Thompson Genetics in
Medicine, 7th Ed （双语版，2009）
● Pages 91-92、168-169、356
Learning Objectives
• To recognize familial patterns of CHD
• To understand developmental
mechanisms of CHD
• To see CHDs as examples of the larger
group of common disorders with
common complex inheritance involving
– Single genes
– Multiple genes
– Environmental influences
Overview
• Introduction to Congenital Heart Disease
(CHD)
• Developmental Mechanisms
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–
–
–
–
Flow Lesions
Problems in Cell Migration
Problems in Cell Death
Abnormalities in Extracellular Matrix
Abnormalities in Targeted Growth
• Summary
Introduction to CHD
• Relatively common birth defect
– Liveborn infants
• 4-8/1 000
– Stillborns
• 10× higher or 8%
– Miscarriages
• 15% in abortuses <24 weeks gestation
Introduction to CHD
• Variety of causes
– Single gene
– Chromosomal
– Teratogen exposures
• Maternal rubella infection
• Gestational diabetes mellitus
Environmental Component
• Maternal Infections
– Rubella: 35% affected
• Maternal Diseases
– Diabetes Mellitus: 3-5%
– Maternal PKU: 10%
• Teratogenic Substances
– Alcohol: 25-35%
– Dilantin（苯妥英）: 2-3%
Genetic Component
• Gross Chromosomal Defects
– 5-8% of Defects
– Examples
• Trisomy 21: 35-50%
• Trisomy 18: 99%
• Turner syndrome: 20%
• Single-Gene Defects
– 3% of Defects
Familial Patterns of Recurrence
• CHD recurrence in a family
– Affected individuals may not have identical
anatomical heart abnormality
– Will have lesions representing similarity in
the developmental mechanism
• Should look for abnormalities outside of
the cardiovascular system
– May indicate a syndromic association with
CHD
Developmental Mechanisms
Flow Lesions
Problems in Cell Migration
Problems in Cell Death
Abnormalities in Extracellular Matrix
Abnormalities in Targeted Growth
Is Isolated CHD a
Multifactorial Trait?
•
•
•
•
Table 8-12: Population
Incidence and
Recurrence Risks for
Various Flow Lesions
VSD = Ventricular
Septal Defect
PDA = Patent Ductus
Arteriosus
ASD = Atrial Septal
Defect
AS = Aortic Stenosis
Defect
Pop
Freq
Incid in Sibs
(%)
(%)
λsib
VSD
0.17
4.3
25
PDA
0.083
3.2
38
ASD
0.066
3.2
48
AS
0.044
2.6
59
Is Isolated CHD a
Multifactorial Trait?
• For these flow lesions
– Sib relative risk ratio (λsib)
• Support familial aggregation
– Where genetic mutation not known
• Use empiric risk factors to counsel first degree relatives
• Rapid decrease in risk for second and third degree relatives to not
much higher than population risks
• For families with CHD other than flow lesions
– Reassure that recurrence risk is no greater than population
risk
• Prenatal ultrasound can be used as part of counseling
and often reassurance before birth
Flow Lesions
• Large category of CHDs
– Approximately 50% of all CHDs
• Up to 25% of flow lesion CHDs,
particularly tetralogy of Fallot, have
del22q11.2
– DiGeorge syndrome
– Velocardiofacial syndrome
– Conotruncal anomaly face syndrome
del22q11.2 Syndromes
• Autosomal dominant
• Variable expressivity
• Deletion of approximately 3 Mb
– Caused by homologous recombination of low
copy repeat sequences
• One of the most common cytogenetic
deletions with a significant phenotype
– 1 per 2 000 – 4 000 live births
22q11.2 Rearrangements
Fig 6-9
del22q11.2 Syndromes
• Phenotypes may include
–
–
–
–
–
–
CHD
Craniofacial abnormalities
Mental retardation/developmental delay
Reduced circulating lymphocytes
Hypocalcemia
Schizophrenia
del22q11.2 and CHD
• Responsible for between 5% and 12.5%
of CHDs
• Particularly common in certain CHDs
– >40% of patients with tetralogy of Fallot
(TOF) and pulmonary atresia (PA)
– >60% of patients with TOF and absent
pulmonary valve
DGS TDR
(Typically Deleted Region)
• 3 Mb deletion
– Loss of approximately 30 genes
• Smaller 1.5 Mb deletion
– Seen in approximately 10% of patients
• TBX1 maps in DGS TDR
– Encodes transcription factor involved in pharyngeal
arch development
– Haploinsufficiency implicated in DGS
– Mutated in patients with similar phenotype who do
not have del22q11.2
Apoptosis and CHD
• TBX1 may be involved in apoptosis, a mechanism
known to be involved in normal cardiac and
lymphocyte development
– Foxp1 in mice
• Required for remodeling of endocardial cushions (portions of
ventricular septum and cardiac outflow tract)
• To position aortic and pulmonary vessels normally by
eliminating certain cells to shift the cushions’ positions
– Apoptosis occurs during immune system development
• To eliminate lymphocytic lineages that react to self
• Required for protection against autoimmune disease
Apoptosis and CHD
• If TBX1 causes the conotruncal defects (e.g.
TOF) associated with del22q11.2, and if the
mechanism is apoptosis, then what does that do
to our “developmental mechanisms” outlined at
the beginning
– del22q11.2 causes the largest proportion of flow
lesions, but may be a problem in cell death
Case #1
4-m.o. Female Infant
– CHF from a Large VSD
– Dysmorphic Appearance
Truncus TOF
Arteriosus
– Family History: Sib and Half-Sib with CHD
– Mother with Multiple Psychiatric Admissions
VSD
DiGeorge Syndrome
• DiGeorge (not DiGeorge’s) Syndrome
• Features Include:
– Cardiac: Conotruncal Defects
– Immunologic: Thymic Aplasia or Hypoplasia
– Hypocalcemia: Parathyroid Absence or Hypoplasia
– Dysmorphism: Hypertelorism, Short Philtrum,
Cupid’s Bow Mouth, Ear Anomalies
VeloCardioFacial (VCF) Syndrome
• Features Include:
– Cardiac: VSD, Tetralogy of Fallot, Rt. Aortic Arch
– Cleft Palate: Overt or Submucosal
– Development Delay: Mild-to-Moderate, esp. Speech
– Dysmorphisms: Prominent Nose, Abnormal Ears,
Abundant Hair, Tapered Fingers
VCF/DG SYNDROMES
Clinical Overlap
Cleft Palate
Dev. Delay
DGS
Cleft Palate
Dev. Delay
VCF Facies
CHD
Dev. Delay
VCF Facies
Problems in Cell Migration:
Patent Ductus Arteriosus (PDA)
• 1 in 2 000 Fullterm Infants
• 10% of CHD
• 2:1 Female to Male Ratio
• Multifactorial Etiology: Genes and Environment
Familial PDA
• 2-y.o. Palestinian Boy
– Patent Ductus Arteriosus
– Positive Family History
PDA
PDA
Neural Crest
Cell
Migration and
Cardiac
Development
Cardiac Genetics
Population Perspective
• Developing Innovative Therapies
– Postnatal Interventions
• Marfan Syndrome: Anti-TGF
– Prenatal Interventions
• Folate
• Improving Clinical Trials Research
– Cardiology Emulating Heme/Onc
– Primary Endpoints - Function, Not Survival
– Better Statistical Power
• First, exome-centered and whole-genome
next-generation sequencing
• Second, epigenetics and transcriptomics
• Third, systems biology
GWAS: the genetic variants identified
often explain 10% of the variation in a
trait or disease!
Epigenetics and Transcriptomics
• Research is increasingly acknowledging
that static DNA sequence variation
explains only a fraction of the inherited
phenotype. Therefore, we expect that
multiple epigenetic and gene expression
signatures will be related to CVD in
experimental and clinical settings.
Complex relationships between the genome,
epigenetic and transcriptional regulations, the
proteome, and the metabolome that produce CVD
phenotypes.
Summary: CHD
• Relatively common birth defect
– 4-8/1 000 live births
• Familial CHD
– May not have identical anatomic
abnormality
• Variety of developmental mechanisms
– Undergoing revision as we understand
molecular pathogenesis
CHD
• Recurrence risk
– If familial, identify inheritance pattern
– If not familial, use empiric risk data
• del22q11.2 is a common cause of CHD
– Up to 25% of flow lesions
– Flow lesions represent 50% of all CHD
– Therefore, 12.5% of all CHD