Genetics of Congenital Heart Disease

Genetics of Congenital Heart Disease

张咸宁[email protected]

Tel ： 13105819271; 88208367 Office: A705, Research Building

2013/03

Required ReadingThompson &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

– 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

• 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%

Environmental 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

Genetic Component

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

Incid (%)

Freq 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 RearrangementsFig 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

4-m.o. Female Infant

– CHF from a Large VSD

– Dysmorphic Appearance

– Family History: Sib and Half-Sib with CHD

– Mother with Multiple Psychiatric Admissions

Case #1

TruncusArteriosus

TOF VSD

• 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

DiGeorge 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

VeloCardioFacial (VCF) Syndrome

VCF/DG SYNDROMESClinical Overlap

Cleft PalateDev. Delay

DGS

Cleft PalateDev. DelayVCF Facies

CHDDev. DelayVCF 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

PDAPDA

Neural Crest Cell Migration and Cardiac Development

Cardiac GeneticsPopulation 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