Genetics of Congenital Heart Disease

Question 1

What is the percentage of pregnancies which end due to the baby of having a cardiac defect?

Answer 1

30%

Question 2

Why is Congenital Heart
Disease a complex genetic disorder?

Answer 2

• One malformation, many genes
• One gene, many malformations

Question 3

What is the cause of a CHD?

Answer 3

• Significant genetic component
• Very few genes identified

Question 4

What kind of genes have been identifies to cause CHD?

Answer 4

• Chromosomal defects
• Syndromes
• Isolated Mendelian:
• Multi-gene interactions

Question 5

What kinds of chromosomal defects cause CHD?

Answer 5

Downs

DiGeorge

CNV

Question 6

What kinds of syndromes cause CHD?

Answer 6

Holt-Oram

Allagille

Question 7

What kinds of mendelian isolated genes cause CHD?

Answer 7

Nkx2.5

Gata4

Notch2

Question 8

What kinds of environmental causes are there for CHD?

Answer 8

• Maternal diabetes
• Drugs
• Pollutants
• Dietary deficiencies

Question 9

What is CHD a result of?

Answer 9

Abnormalities in normal cardiac development

Question 10

How long are human pregnancies?

Answer 10

38-40 weeks

Question 11

When does organogenesis occur?

Answer 11

Embryogenesis

Question 12

When does severe CHD occur?

Answer 12

First 6 weeks of pregnancy

Question 13

When does milder versions of CHD occur?

Answer 13

6-9 weeks pregnant

Question 14

When happens in heart development at 5 weeks?

Answer 14

The heart is practically fully formed.

Question 15

Are genes that form and maintain the heart conseved?

Answer 15

YES

Question 16

What kinds of chromosomal defects cause CHD?

Answer 16

Down syndrome

Turner syndrome

Question 17

How many down syndrome suffers have CHD?

Answer 17

60%

Question 18

Where is the critical region for Down syndrome and CHD?

Answer 18

0.96 Mb on 21q22.2

Question 19

What genes does the critical region for Down syndrome and CHD contain?

Answer 19

DSCAM,

COL6A1

COL6A2,

KCNJ6

RCAN1

Question 20

How often do CHDs happen when a perosn has turner syndrome?

Answer 20

60%

Question 21

Where is the CHD critical region for turner syndrome?

Answer 21

Short arm of X

Question 22

Why is CHD during turner syndrome so dangerous?

Answer 22

Global hypomethylation of genome so genes outside X also affected.

Question 23

What percentage of patients with DiGeorge syndrome have CHD?

Answer 23

50%

Question 24

What is the risk gene for CHD in DiGeorge syndrome?

Answer 24

TBX1

Question 25

What is heterotaxy?

Answer 25

A rare birth defect that involves the heart and other organs.

Question 26

How many of CHD cases are due to cilia defects?

Answer 26

60%

Question 27

What happens to the occurrence of heterotaxy when the mother has diabetes?

Answer 27

Increases 8 times.

Question 28

How many single genes causing CHD have been idetifies?

Answer 28

25

Question 29

How are genes cuasing CHD found?

Answer 29

GWAs WES

Question 30

What was proved using WES about syndromic CHD patients?

Answer 30

They showed a large amount of de novo mutated genetics compared to their parents.

Question 31

What was proved using WES about non-syndromic CHD patients?

Answer 31

Genes were inherited from parents but the parents are unaffected.

Question 32

In the large genomic studies of CHD patients were discovered to have a large link to CHD?

Answer 32

CHD4 CDK13 PRKD1

Question 33

How to filter out CHD patients' genthe omic data?

Answer 33

* Familial cases * Replicated in multiple studies * Online databases prediction * Known role in cardiac development * Variant validated by in vitro assay or animal model

Question 34

What is TAA?

Answer 34

Thoracic aortic aneurism is a disease of the ascending part of aorta.

Question 35

When does TAA happen?

Answer 35

Symptomatic in children, non in adults. Sometimes congenital.

Question 36

What is the mortality for TAA?

Answer 36

90%

Question 37

What is aortic disscetion?

Answer 37

The aorta splits during TAA.

Question 38

What kinds of genes cause TAA?

Answer 38

Components of smooth muscle cells or connective tissue TGFb signalling pathway

Question 39

What is BAV?

Answer 39

Abnormal leaflet formation in the heart.

Question 40

What is the incidence rate for BAV?

Answer 40

2%

Question 41

What diseases are linked to BAV?

Answer 41

TAA Calcific valve disease

Question 42

What genes cause BAV?

Answer 42

ROBO4

Question 43

What mechanisms underpin BAV?

Answer 43

Absence of intercalating cushion. Excess fusion of free edges. Mispositioned cushions lead to excessive fusion of free edges.

Question 44

What is HLHS?

Answer 44

Severe CHD disease but survivable, small left ventricle so the heart doesn't pump very hard.

Question 45

How is HLHS diagnosed?

Answer 45

Echocardiography

Question 46

What is the treatment for HLHS?

Answer 46

* Termination of pregnancy * Major palliative surgery (3 ops) * Transplantation

Question 47

What is the issue with surgery for HLHs?

Answer 47

* 3 operations in first five years * 70% survival to this stage * Survival beyond 40 is rare * Cause remains unclear