Genetics of congenital heart disease
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Genetics of Congenital Heart Disease. 张咸宁 [email protected] Tel: 13105819271; 88208367 Office: A705, Research Building 2012/02. Required Reading. Thompson &Thompson Genetics in Medicine, 7 th Ed (双语版, 2009 ) ● Pages 91-92 、 168-169 、 356

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Genetics of Congenital Heart Disease

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Genetics of congenital heart disease

Genetics of Congenital Heart Disease

张咸宁

[email protected]

Tel:13105819271; 88208367

Office: A705, Research Building

2012/02


Required reading

Required Reading

Thompson &Thompson Genetics in Medicine, 7th Ed (双语版,2009)

● Pages 91-92、168-169、356

Recommended: Weissman CG and Gelb BD. The genetics of congenital heart disease: a review of recent developments. Curr Opinion Cardiol 2007; 22:200-206.

Kaltman JR, et al. Circulation 2010;121:2766-72.

Kaltman JR, et al. Journal of the American College of Cardiology 2010;56:1262–5.


Learning objectives

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

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

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 chd1

Introduction to CHD

Variety of causes

Single gene

Chromosomal

Teratogen exposures

Maternal rubella infection

Gestational diabetes mellitus


Genetics of congenital heart disease

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%

Congenital Heart DefectsEnvironmental Component


Genetics of congenital heart disease

Gross Chromosomal Defects

5-8% of Defects

Examples

Trisomy 21: 35-50%

Trisomy 18: 99%

Turner syndrome: 20%

Single-Gene Defects

3% of Defects

Congenital Heart DefectsGenetic Component


Familial patterns of recurrence

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

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

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


Is isolated chd a multifactorial trait1

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 fig 8 9

Flow LesionsFig 8-9


Flow lesions

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

del22q11.2 Syndromes

Autosomal dominant

Variable expressivity

Deletion of approximately 3Mb

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


Unequal crossing over due to homologous recombination fig 6 8

Unequal Crossing Over Due to Homologous RecombinationFig 6-8


Genetics of congenital heart disease

22q11.2 Rearrangements

Fig 6-9


Del22q11 2 syndromes1

del22q11.2 Syndromes

Phenotypes may include

CHD

Craniofacial abnormalities

Mental retardation/developmental delay

Reduced circulating lymphocytes

Hypocalcemia

Schizophrenia


Sidebar del22q11 2 and schizophrenia

Sidebar: del22q11.2 and Schizophrenia

An estimated 25% of patients with del22q11.2 develop this

Even in the absence of many or most of the physical signs of DGS

1 per 2-4,000 live births with del22q11.2

Therefore, 1 per 8-16,000 live births may develop schizophrenia due to this deletion

Most common genetic mechanism for schizophrenia known at this time

Mechanism is unknown


Del22q11 2 and chd

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

DGS TDR(Typically Deleted Region)

3Mb 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

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 chd1

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

See a shift in concepts of pathogenesis

From a physiological view (flow)

To a molecular view (defect in apoptosis)


Genetics of congenital heart disease

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

Truncus

Arteriosus

TOF

VSD


Genetics of congenital heart disease

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


Genetics of congenital heart disease

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


Genetics of congenital heart disease

VCF/DG SYNDROMESClinical Overlap

Cleft Palate

Dev. Delay

VCF Facies

Cleft Palate

Dev. Delay

DGS

CHD

Dev. Delay

VCF Facies


Genetics of congenital heart disease

Deleted

Chr 22

Normal

Chr 22

FISH for

del22q11.2

Detects 85-90%

of patients


Molecular cytogenetics

Molecular Cytogenetics

Single nucleotide polymorphism microarrays (SNP chips) can determine copy number variations (CNVs)

Billions of features to evaluate 2M SNPs on a chip


Constructing and analyzing microarrays

Constructing and Analyzing Microarrays

Photolihography


Dna match vs mismatch

DNA: Match vs. Mismatch

Match

Double Stranded DNA

Hybridize

Heat

Hybridize

Heat

Single Stranded DNA

Mismatch


Microarray match vs mismatch

Microarray: Match vs. Mismatch

Labeled Target

Match

Target DNA

Captured

Hybridize

Heat

Wash

Attached

Capture

Probe

Hybridize

Heat

Wash

Target DNA

Lost

Mismatch


Microarray analyses

Microarray Analyses

SNPs

AA, AB and BB

Where A and B are A, T, G or C

Original use: genome-wide association studies (GWAS)

Software can determine if

A/null or B/null

Copy number variations (CNVs)


Options in whole genome analysis

Options in Whole Genome Analysis

Current genome sequencing

Complete Genomics (Mountain View, CA)

Announced February 5, 2010

Beginning June 2010, offering sequencing at $5,000/genome (http://www.bloomberg.com/apps/news?sid=aEUlnq6ltPpQ&pid=20601124#)

NHGRI: Revolutionary Sequencing Technologies – The $1,000 Genome (R01)

SNP (Single Nucleotide Polymorphism) Microarrays

Affymetrix 6.0 array

>906,600 SNPs

>946,000 Copy Number Probes (CNPS)

Human Genome Project, 2003

First genome sequenced in 3 yrs

At a cost of $2.5B


Whole genome analysis

Whole Genome Analysis

CNPs

202,000 probes targeting 5,677 known CNV regions

744,000 evenly spaced probes across the genome

Overall

Average approximately 1probe/1,500 bp

Median inter-marker spacing of 696 bp

http://www.sanger.ac.uk/humgen/cnv/data/


Genetics of congenital heart disease

Whole Genome Data Is Acquired

Patient below without any known genetic disease

All chromosomes but Y represented


Genetics of congenital heart disease

Five patients with del22q11.2 show similar 3 Mb TDR

Not seen in five patients without del22q11.2 syndrome

Multiple Patients with del22q11.2 Syndrome

Show Similar Deletions in DGCR


Whole genome analysis1

Whole Genome Analysis

Microarrays

Proxy for genomic sequencing

Learning to live with

Uncertainty

Error vs. benign change

Correlations with clinical findings

Huge volumes of data

Storage

Processing


Dna hybridization as nanotechnology

DNA Hybridization as Nanotechnology

SNP Microarrays or “SNP Chips”

NanoPediatrics core uses the Affymetrix platform

SNP “feature” is a 20-mer that will identify a specific SNP

If SNP present in person’s DNA, then form a double helix in the chip

The double helix shown here is made up of hybridized 20-mers

Each 20-mer in the double helix configuration is 6.8 nm long with a diameter of 2 nm


Whole genome microarrays clinical diagnostics

Whole Genome Microarrays: Clinical Diagnostics

UCLA

Medical Genetics using this technology clinically since 2006

September 1, 2009 announced Personalized Genetics Medicine Center

Joint venture between Pathology and Pediatrics

Integrates laboratory diagnostic and genetic counseling services

Important to gain this experience as we approach the clinical use of whole genome sequencing


Genetics of congenital heart disease

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

Familial PDA

2-y.o. Palestinian Boy

Patent Ductus Arteriosus

Positive Family History

PDA

PDA


Genetics of congenital heart disease

Char Syndrome

  • Described in 1978 by Florence Char, Univ of Arkansas

  • Features

    • Patent Ductus Arteriosus (PDA)

    • Facial Dysmorphism

    • 5th Finger Abnormalities

  • Autosomal Dominant Inheritance

    • Complete Penetrance

    • Variable Expression


Genetics of congenital heart disease

CHAR SYNDROME


Genetics of congenital heart disease

ARKANSAS CHAR KINDRED

I

II

III

1

2

3

4

5

6

7

IV

1

2

3

4

5

6

7

8

9

10

12

13

14

15

16

17

18

19

20

21

22

23

24

25

V

9

1

2

3

4

5

6

7

8

10

11

12

13

14

15

16

17

18

19

VI

1

2

3

4

5

6


Char syndrome disease gene discovery

Char SyndromeDisease Gene Discovery

Linked to Chromosome 6p12

Candidate Gene Approach

Transcription Factor AP-2b

Relevant for Neural Crest Development

Missense Mutations in Several Unrelated Patients

Dominant Negative Mechanism


Neural crest cell migration and cardiac development

Neural Crest Cell Migration and Cardiac Development


Cardiac genetics population perspective

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


Summary chd

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


Genetics of congenital heart disease

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


Acknowledge ppt

Acknowledge(PPT特别鸣谢!)

  • UCLA David Geffen School of Medicine

  • www.medsch.ucla.edu/ANGEL/

  • Prof. McCabe E (Mattel Children’s Hospital UCLA; Dept of Pediatrics, Human Genetics, and Bioengineering, UCLA), et al.


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