Imprinting Disorders ✅ Flashcards
How are imprinted genes different from normal?
Normally, we inherit 1 copy of a gene from each parent and both are active. With imprinted genes, only the copy from one parent is expressed
Does everyone have some imprinted genes?
Yes, having imprinted genes is normal
How are imprinted genes often arranged?
In clusters
Is it the maternal or paternal copy that is active in imprinted genes?
Can be either
What is found within one cluster of imprinted genes?
Some genes are expressed only from the maternally inherited copy, and are silent on the paternally inherited copy.
Others are expressed only from the paternal copy, and silent from the maternal copy.
What is the process of imprinting controlled by?
‘Epigenetic’ factors such as DNA methylation
How does DNA methylation control imprinting?
It occurs in imprinted regions in a ‘parent-of-origin’ specific manner
What can disruption of normal imprinting lead to?
A number of diseases
What are the mechanisms that can cause imprinting disorders?
- Methylation defect
- Uniparental disomy (UPD)
- Deletion
- Single gene mutation
How can a methylation defect lead to an imprinting disorder?
Abnormalities of the normal methylation pattern in an imprinted region can disrupt the normal parent-of-origin specific expression pattern
How can abnormalities of the normal methylation pattern in an imprinted region disrupt the normal parent-of-origin specific expression pattern?
Either by switching off genes which are normally active, or switching on genes which are normally silenced
What is uniparental disomy?
Inheritance of both copies of a chromosome or chromosome region from the same parent
What happens to the imprinted expression patterns of genes when there is uniparental disomy?
They remain the imprinted expression pattern of the parent of origin
How can a deletion cause an imprinting disorder?
Deletion of an imprinted region
What does the effect of the deletion of an imprinted region depend on?
The parent of origin of the chromosome carrying the deletion
How can a single gene mutation lead to an imprinting disorder?
A loss of function mutation in imprinted disease genes
What must be true for a loss of function mutation to cause an imprinting disorder?
It must be present on the copy of the gene that is normally active
Which of the mechanisms of imprinting disorders are inheritable?
Deletions and single gene mutations
Why are uniparental disomy and methylation defects not inheritable?
They are ‘epigenetic’ alterations i.e. they do not involve alteration in the DNA sequence
How are methylation defects and uniparental disomy causing imprinting disorders acquired?
De novo mutations
What is the implication of uniparental disomy and methylation defects being caused by only de novo mutations on the risk of recurrence?
They have low risks of recurrence
How are deletions and single gene mutations causing imprinting disorders acquired?
Either inherited or de novo
What is the inheritance pattern of imprinting disorders caused by deletions or single gene mutations?
Autosomal dominant inheritance
How is the inheritance of deletions and single gene mutations causing imprinting disorders different to that of other autosomal dominant conditions?
It will only cause disease when inherited from the parent whose copy of the gene is normally active
What does the method of testing for imprinting disorders depend on?
The mechanisms relevant to the disorder in questions
How are imprinting disorders caused by methylation defects tested for?
Methylation testing using techniques such as methylation-specific PCR or MLPA (a multiplex PCR)
What is the advantage of methylation-specific PCR or MLPA in testing for imprinting disorders?
It is capable of detecting methylation defects, uniparental disomy, and deletions
Why is methylation-specific PCR or MLPA capable of detecting uniparental disomy and deletions?
Because they result in altered DNA methylation patterns by removing one of the parental copies of the region
What is the clinical relevance of methylation-specific PCR or MLPA being able to detect methylation defects, uniparental disomy, and deletions?
It is often the first line test for imprinting disorders
How can uniparental disomy testing be performed?
Micro-satellite analysis (DNA fingerprinting) using samples from the child and both parents
What techniques can be used to test for deletions causing imprinting disorders?
- Genome-wide microarray
- MLPA
When is genome-wide microarray appropriate for testing for deletions causing imprinting disorders?
When looking for large deletions
When are more targeted techniques such as MLPA appropriate for testing for deletions causing imprinting disorders?
When looking for smaller deletions
What is used to test for single gene mutations causing imprinting disorders?
DNA sequencing of imprinted genes
