Genetics of Congenital Heart Disease Flashcards
What is the percentage of pregnancies which end due to the baby of having a cardiac defect?
30%
Why is Congenital Heart
Disease a complex genetic disorder?
- One malformation, many genes
- One gene, many malformations
What is the cause of a CHD?
- Significant genetic component
- Very few genes identified
What kind of genes have been identifies to cause CHD?
- Chromosomal defects
- Syndromes
- Isolated Mendelian:
- Multi-gene interactions
What kinds of chromosomal defects cause CHD?
Downs
DiGeorge
CNV
What kinds of syndromes cause CHD?
Holt-Oram
Allagille
What kinds of mendelian isolated genes cause CHD?
Nkx2.5
Gata4
Notch2
What kinds of environmental causes are there for CHD?
- Maternal diabetes
- Drugs
- Pollutants
- Dietary deficiencies
What is CHD a result of?
Abnormalities in normal cardiac development
How long are human pregnancies?
38-40 weeks
When does organogenesis occur?
Embryogenesis
When does severe CHD occur?
First 6 weeks of pregnancy
When does milder versions of CHD occur?
6-9 weeks pregnant
When happens in heart development at 5 weeks?
The heart is practically fully formed.
Are genes that form and maintain the heart conseved?
YES
What kinds of chromosomal defects cause CHD?
Down syndrome
Turner syndrome
How many down syndrome suffers have CHD?
60%
Where is the critical region for Down syndrome and CHD?
0.96 Mb on 21q22.2
What genes does the critical region for Down syndrome and CHD contain?
DSCAM,
COL6A1
COL6A2,
KCNJ6
RCAN1
How often do CHDs happen when a perosn has turner syndrome?
60%
Where is the CHD critical region for turner syndrome?
Short arm of X
Why is CHD during turner syndrome so dangerous?
Global hypomethylation of genome so genes outside X also affected.
What percentage of patients with DiGeorge syndrome have CHD?
50%
What is the risk gene for CHD in DiGeorge syndrome?
TBX1
What is heterotaxy?
A rare birth defect that involves the heart and other organs.
How many of CHD cases are due to cilia defects?
60%
What happens to the occurrence of heterotaxy when the mother has diabetes?
Increases 8 times.
How many single genes causing CHD have been idetifies?
25
How are genes cuasing CHD found?
GWAs
WES
What was proved using WES about syndromic CHD patients?
They showed a large amount of de novo mutated genetics compared to their parents.
What was proved using WES about non-syndromic CHD patients?
Genes were inherited from parents but the parents are unaffected.
In the large genomic studies of CHD patients were discovered to have a large link to CHD?
CHD4
CDK13
PRKD1
How to filter out CHD patients’ genthe omic data?
- Familial cases
- Replicated in multiple studies
- Online databases prediction
- Known role in cardiac development
- Variant validated by in vitro assay or animal model
What is TAA?
Thoracic aortic aneurism is a disease of the ascending part of aorta.
When does TAA happen?
Symptomatic in children, non in adults.
Sometimes congenital.
What is the mortality for TAA?
90%
What is aortic disscetion?
The aorta splits during TAA.
What kinds of genes cause TAA?
Components of smooth muscle cells
or connective tissue
TGFb signalling pathway
What is BAV?
Abnormal leaflet formation in the heart.
What is the incidence rate for BAV?
2%
What diseases are linked to BAV?
TAA
Calcific valve disease
What genes cause BAV?
ROBO4
What mechanisms underpin BAV?
Absence of intercalating cushion.
Excess fusion of free edges.
Mispositioned cushions lead to excessive fusion of free edges.
What is HLHS?
Severe CHD disease but survivable, small left ventricle so the heart doesn’t pump very hard.
How is HLHS diagnosed?
Echocardiography
What is the treatment for HLHS?
- Termination of pregnancy
- Major palliative surgery (3 ops)
- Transplantation
What is the issue with surgery for HLHs?
- 3 operations in first five years
- 70% survival to this stage
- Survival beyond 40 is rare
- Cause remains unclear
