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
What is the result of paternal UPD for the full chromosome complement?
Complete hydatidiform mole
What is the result of maternal UPD for the full chromosome complement?
Benign cystic ovarian teratoma
Why is UPD commonly mosaic?
Trisomy or monosomy rescue happens post-zygotically
Trisomic cell line is often confined to the placenta (CPM)
The mechanism of generation of segmental isodisomy results in mosaicism for mat UPID and pat UPD. Why do BWS patients only show pat UPID11p15.5?
Maternal UPID 11p15.5 is lethal - these cells aren’t viable
Why might UPD along the length of a chr pair be a mix of UPHD and UPID?
Due to recombination in meiosis I
What is UPD14 associated with?
Maternal UPD14 = Temple syndrome
Paternal UPD14 = Kagami-Ogata syndrome
What is UPD7 associated with?
Maternal UPD7 causes approx 10% of RSS cases
Heterodisomy and isodisomy, segmental UPD reported
How is UPD7 tested for?
What genes are tested and why?
MS-MLPA
GRB10 and MEST both methylated on maternal allele - gain of methylation = mat UPD7
What gene is tested for in UPD14? What is the methylation pattern?
MEG3
Methylated on paternal allele:
- loss of methylation = matUPD14
- gain of methylation = patUPD14
How do Robsertsonian translocations behave at meiosis?
Synapse with the 2 normal homologs as a trivalent
Results in 2:1 segregation
What is the result of alternate segregation for a ROB?
Normal gamete & ROB carrier gamete (balanced)
What is the result of adjacent segregation for a ROB?
Only unbalanced disomic and nullsomic gametes
Give an example of when a balanced rearrangement disrupts imprinting
Maternal t(7;16) associated with maternal heterodisomy (mat UPD7) in Russel Silver syndrome due to 3:1 segregation and trisomy rescue
