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
Give 5 examples of imprinting disorders
- Prader-Willi syndrome
- Angelman syndrome
- Beckwith-Wiedemann syndrome
- Albright’s hereditary osteodystrophy
- Transient neonatal diabetes mellitus
What is the incidence of Prader-Willi syndrome?
1 in 10,000-20,000
What is Prader-Willi syndrome caused by?
Abnormalities at the imprinted 15q11 Prader-Willi/Angelman syndrome region
What can cause the genetic abnormalities in Prader-Willi syndrome?
- Maternal uniparental disomy at chromosome 15q11
- Large deletions of paternal copy of 15q11
- Methylation defects
What % of cases of Prader-Willi syndrome are caused by maternal uniparental disomy at chromosome 15q11?
25%
What % of cases of Prader-Willi syndrome are caused by large deletions of the paternal copy of 15q11?
70%
What % of cases of Prader-Willi syndrome are caused by methylation defects?
<1%
How to the genetic changes in Prader-Willi syndrome compare to those in Angelamn syndrome?
They are reciprocal
Are the genetic abnormalities in Prader-Willi syndrome inherited or de novo?
They are usually inherited
What are the features of Prader-Willi syndrome?
- Hypotonia and poor feeding in the neonatal period
- Mild to moderate learning difficulties
- Hyperphagia and obesity
- Hypogonadotrophic hypogonadism
At what age to hyperplasia and obesity develop in Prader-Willi syndrome?
12-18 months
What % of males with Prader-Willi syndrome have hypogonadotrophic hypogonadism?
> 80%
How is Prader-Willi syndrome diagnosed?
Molecular genetic testing by methylation testing followed by microarray (for deletions) and uniparental disomy testing as appropriate
What is the incidence of Angelman syndrome?
1 in 10,000
What is Angelman syndrome caused by?
Abnormalities at the imprinted 15q11 Prader-Willi/Angelman syndrome region that inactivates the UBE3A gene
Is the UBE3A gene normally active on the paternal or maternal allele?
Maternal
What are the main mechanisms of genetic abnormality causing Angelman syndrome?
- Paternal uniparental disomy at chromosome 15q11
- Large deletions of maternal copy of 15q11
- Loss of function mutations on maternal allele of UBE3A
What % of cases of Angelman syndrome are caused by paternal uniparental disomy at chromosome 15q11?
10%
What % of cases of Angelman syndrome are caused by large deletions of the maternal copy of 15q11?
70%
What % of cases of Angelman syndrome are caused by loss of function mutations on the maternal allele of UBE3A?
10%
What cause of Angelman syndrome is usually inherited?
UBE3A mutations
From what parent are UBE3A mutations inherited?
Mother
What is the risk of recurrence when Angelman syndrome is caused by UBE3A mutations?
50%
How are other genetic abnormalities causing Angelman syndrome acquired?
Usually de novo
What is the risk of recurrence of Angelman syndrome that occurs due to de novo mutations?
Low
How does Angelman syndrome present?
- Severe developmental delay
- Ataxia
- Behavioural phenotype - happy disposition
- Characteristic appearance
- Seizures
What % of children with Angelman syndrome have seizures?
> 80%
What is the characteristic appearance of Angelman syndrome?
- Wide mouth
- Microcephaly
- Fair skin and hair colour
Why do some children with Angelman syndrome have fair skin and hair colour?
Due to the presence of a pigment gene near the Angelman syndrome region
How is Angelman syndrome diagnosed?
Molecular genetic testing by methylation testing following by microarray (for deletions) and uniparental disomy testing as appropriate
What is done in suspected Angelman syndrome when methylation is normal but the diagnosis is still considered likely?
UBE3A sequencing
What is the incidence of Beckwith-Wiedemann syndrome?
1 in 10,000
What is Beckwith-Wiedemann syndrome caused by?
Abnormalities at the imprinted 11p15 growth regulatory region
What are the mechanisms of genetic abnormality causing Beckwith-Wiedemann syndrome?
- Decreased methylation
- Increased methylation
- Paternal uniparental disomy
- Loss of function mutation on the maternal allele
In what region can deceased methylation cause Beckwith-Wiedemann syndrome?
KvDMR region
What % of cases of Beckwith-Wiedemann syndrome are caused by decreased methylation at the KvDMR region?
50%
In what region can increased methylation cause Beckwith-Wiedemann syndrome?
At the H19 region
What % of cases of Beckwith-Wiedemann syndrome are caused by increased methylation at the H19 region?
5%
At what location can paternal uniparental disomy cause Beckwith-Wiedemann syndrome?
11p15
What % of cases of Beckwith-Wiedemann syndrome are caused by paternal uniparental disomy at chromosome 11q15?
20%
At what location can loss of function mutations on the maternal allele cause Beckwith-Wiedemann syndrome?
CDKN1C
What % of cases of Beckwith-Wiedemann syndrome are caused by a loss-of-function mutation of the maternal allele of CDKN1C?
5%
How do the abnormalities seen in Beckwith-Wiedemann syndrome compare to those seen in Silver-Russell syndrome?
They are reciprocal
How are methylation defects and uniparental disomy acquired in Beckwith-Wiedemann syndrome?
Usually occur de novo
How are CDKN1C mutations causing Beckwith-Weidemann syndrome usually acquired?
Inherited from patients mother
What is the inheritance pattern of CDKN1C mutations causing Beckwith-Wiedemann syndrome?
Autosomal dominant
What are the clinical features of Beckwith-Wiedemann syndrome?
- Pre and postnatal overgrowth
- Neonatal hypoglycaemia
- Coarse facial features
- Macroglossia
- Exomphalos or umbilical hernia
- Hemihypertrophy
- Earlobe creases and posterior helical pits
- Increased risk of tumours
Does Beckwith-Wiedemann syndrome affect intelligence?
No (providing neonatal hypoglycaemia is avoided)
What kind of tumours are patients with Beckwith-Wiedemann syndrome at increased risk of?
Embryonal tumours, mainly Wilms’ tumour
Is the risk of Wilm’s tumour increased in all patients with Beckwith-Wiedemann syndrome?
No, only in some molecular subgroups
In what molecular subgroup of Beckwith-Wiedemann syndrome is the risk of Wilm’s tumour not increased?
KvDMR methylation defects
What should be done due to the risk of Wilm’s tumour in all patients with Beckwith-Wiedemann syndrome who are not in the KvDMR methylation defect subgroup?
Renal ultrasound scans every 3-4 months until 7 years
What is the purpose of molecular genetic testing in Beckwith-Wiedemann syndrome?
- Confirmation of diagnosis
- Assessment of tumour risk
