22. Origin of UPD - mechanisms and detection methods Flashcards
What is UPD?
Uniparental disomy
2 copies of all/part of a chromosome from one parent and no copies from other
Why can UPD cause disease?
- Disruption of imprinted regions (6, 7, 11, 14, 15, 20) –> 2 active parental alleles or 2 silent parental alleles depending on contributing parent
- Creates an AR condition if isodisomy
Why can UPD cause miscarriage?
- If localised to regions of chromosomes with imprinted genes which control embryogenesis and fetal development
- Isodisimy - activates a recessive mutation in genes which are essential for early embryogenesis
What is UPHD?
Uniparental heterodisomy
Presence of both homologues from the transmitting parent
How does UPHD occur?
Likely meiosis I non-disjunction (failure of homologues to separate)
What is UPID?
Uniparental isodisomy
Presence of 2 identical copies of 1 of the parental homologues (sister chromatid)
How does UPID occur?
Likely meiosis II non-disjunction (failure of sister chromatids to separate)
or mitotic error
What is the main mechanism by which UPD of a whole chromosome occurs?
Trisomy rescue:
- Meiotic non-disjunction in one parent gives disomic gamete:
- Meiosis I - failure of homologues to separate –> UPHD
- Meiosis II - failure of sister chromatids to separate –> UPID - Fertilisation results in trisomic fetus, post-zygotic loss of one homolog by anaphase lag or mitotic non-disjunction leads to UPD in 1/3 cases
What are the less common mechanisms that lead to UPD of a whole chromosome?
Monosomic rescue - nullsomic gamete + normal haploid gamete, rescued by mitotic non-disjunction or duplication (rarer than trisomy rescue)
Gamete complementation - meiotic non-disjunction in both parents. Disomic gamete from 1 parent, nullsomic from other
What is segmental UPD?
UPD for part of one chromosome pair, biparental inheritance for the rest of the pair
Give an example of segmental UPD in disease
Mosaicism for partial paternal isodisomy of 11p15.5
10-20% of BWS cases
How does segmental isodisomy arise?
Post-zygotically due to mitotic exchange between non-sister chromatids
Means that UPD should be present in each daughter cell - maternal UPID in one and paternal UPID in the other one (mosaicism)
When is the risk of UPD increased and why?
In carriers of:
a) Robertsonian translocation
b) Reciprocal translocations at risk of 3:1 non-disjunction
Both cause increased risk of malsegregation leading to disomic or nullsomic gamete
Post-zygotic trisomy or monosomy rescue can lead to UPD
In what scenarios is UPD testing recommended?
If familial chr. rearrangement involves an imprinted chr.
If variant in AR gene is homozygous but only 1 parent is a carrier
How is UPD tested for?
What are the limitations of each?
Directly:
Microsatellite analysis - F-PCR of STRs in parents and proband, can distinguish between UPID and UPHD
SNP array can detect isodisomy, not heterodisomy
Trio WES/WGS can identify regions of homozygosity and distinguish between biparental homozygosity and isodisomy
Indirectly:
If an imprinted chromosome is affected: Bisulphite modification, MS-PCR and MS-MLPA - detect change in methylation status
