12. BWS/RSS Flashcards

1
Q

What is the result of DNA methylation?

A

Repressing/silencing transcription

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2
Q

Which residues can be methylated? What is the mechanism?

A

Cytosine residues with a downstream neighbouring guanine residue (CpG islands)

Methly group added to cytosine residue to produce 5-methylcytosine

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3
Q

What is the definition of imprinting?

A

Genes that are differentially methylated depending on their parent of origin

Leads to monallelic, parent-specific gene expression

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4
Q

When are imprinting patterns erased?

A

During the development of the parental gametes for transmission to offspring

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5
Q

What are the clinical features of BWS?

A

Overgrowth, macroglossia, exomphalos, hemihyperplasia, Wilms tumour (nephroblastoma), macrosomia

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6
Q

What are the clinical features of RSS?

A

Severe intrauterine and postnatal growth retardation, short stature, characteristic triangular facies, body asymmetry

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7
Q

What is the BWS/RSS critical region?

A

11p15

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8
Q

What are the 2 ICs at 11p15 and what genes do the regulate expression of?

A

IC1/H19DMR - IGF2 & H19

IC2/KvDMR - CDKN1C, KCNQ1, KCNQ1OT1

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9
Q

Describe the methylation pattern of IC1/H19DMR

A

IC1 methylated on paternal chromosome, unmethylated on maternal chromosome

Paternal chr - H19 suppressed, IGF2 expressed

Maternal chr - H19 expressed, IGF2 suppressed

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10
Q

What are the roles of IFG2 and H19?

A

IGF2 - fetal growth factor (regulates cell proliferation, growth, migration, differentiation and survival)

H19 - non-coding RNA thought to act as tumour supressor

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11
Q

Describe the methylation pattern of IC2/KvDMR

A

IC2 unmethylated on paternal chromosome, methylated on maternal chromosome

Paternal chr - KCNQ1OT1 expressed, KCNQ1 & CDKN1C suppressed

Maternal chr - KCNQOT1 suppressed, KCNQ1 & CDKN1C expressed

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12
Q

What proportion of BWS cases are sporadic vs inherited?

A

85% sporadic, 15% inherited (AD)

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13
Q

What is the most common cause of sporadic BWS?

A

Loss of methylation (hypomethylation) at maternal IC2/kvDMR

Approx 50% of cases

Causes loss of CDKN1C (and KCNQ1) expression –> overgrowth, increased expression of KNCQ1OT1

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14
Q

What is the second most common cause of sporadic BWS?

What does it result in?

A

Mosaic paternal UPD11p15 - segmental isodisomy

Approx. 20% of cases

Hypermethylation of IC1 AND hypomethylation of IC2

Increased IGF2 expression, decreased CDKN1C expression

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15
Q

What causes paternal UPD11p15 in BWS and why is it always mosaic?

A

Post-zygotically due to mitotic exchange between non-sister chromatids in early embryogenesis

Means that UPD should be present in each daughter cell - maternal UPID in one and paternal UPID in the other one (mosaicism)

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16
Q

Why is mosaicism for mat and pat segmental isodisomy not seen in BWS?

A

Because maternal isodisomy is lethal

17
Q

What is the third most common cause of sporadic BWS?

A

Gain of methylation (hypermethylation) at maternal IC1/H19DMR

Approx. 10% of cases

Causes loss of H19 expression + increased expression of IGF2

18
Q

What is the role of CTCF?

A

Regulates expression of IGF2 and H19 by creating chromatin loops

Unmethylated maternal allele, CTCF binds IC1 to HIDAD - H19 under control of enhancer & expressed, acts as an insulator and prevents IGF2 from being expressed

Methylation on paternal allele prevents CTCF from binding IC1 to HIDAD –> forms alternative loop so that IGF2 can be activated by enhancers

19
Q

Why do mutations in CTCF binding sites result in BWS?

A

Cause paternal pattern of DNA looping on both chromosomes - IGF2 activated by enhancers and so is expressed biallelically, H19 not expressed from maternal allele

20
Q

What is the recurrence risk associated with CTCF binding site mutations?

21
Q

What are the fourth and fifth most common causes of BWS?

A
  1. Maternal CDKN1C point mutations (5% of sporadic, 40% of familial)
  2. Duplications and deletions at 11p15 - must have an accompanying methylation change
22
Q

What is the role of CDKN1C?

A

Negative regulator of cell proliferation - inhibits cyclin/cyclin-dependent complexes of the G1 phase

Expressed from maternal allele - loss results in overgrowth seen in BWS

Mutations in maternally inherited allele cause BWS

23
Q

In a patient with ?BWS, what does a normal MS-MLPA result indicate?

A

CDKN1C testing

Pathogenic variants have high recurrence risk

24
Q

When is SNP array required?

A
  1. Deletion & methylation change on MS-MLPA - define breakpoints
  2. GOM at IC1 and LOM at IC2 - suggestive of pat isodisomy UPD11, array to confirm
  3. Borderline methylation result for IC1 and IC2 - ?pat UPD11
25
In a patient referred for BWS, what is the result of a CNV + methylation abberation on MS-MLPA?
Confirms BWS Suggest array & parental testing to determine size of CNV & inheritance High recurrence risk
26
What are the two causes of RSS?
11p15 related chr 7 related
27
What is the chr 7 related cause of RSS?
Maternal UPD7 Approx 10% of cases Heterodisomy and isodisomy, segmental UPD reported
28
How is UPD7 tested for? What genes are tested and why?
MS-MLPA GRB10 and MEST both methylated on maternal allele - looking for gain of methylation
29
What gene is tested for in UPD14? What is the methylation pattern?
MEG3 Methylated on paternal allele - loss of methylation = matUPD14
30
What is paternal UPD14 associated with?
Kagami-Ogata syndrome
31
What are the three 11p15 related causes of RSS? Which is most common?
IC1 hypomethylation is most common (40-60%) - loss of methylation on paternal allele --> no IGF2 expression Deletion/duplication at 11p15 Maternal UPD11
32
What is the significance of UPD14?
Maternal UPD14 associated with Temple syndrome which has phenotypic overlap with RSS
33
Which form of BWS is MLID associated with?
33% of BWS cases caused by loss of methylation at maternal IC2/kvDMR Usually no added clinical features from having aberrant methylation at other loci
34
What is MLID?
Multi locus imprinting disorder Aberrant methylation at multiple imprinted loci across the genome
35
Give an example of a disorder with a high proportion of MLID
Transient Neonatal Diabetes Up to 60% of cases show MLID
36
Why might BWS be indicated prenatally?
Exomphalos often detected in the first trimester scan
37
What sample type is required for prenatal BWS testing & why?
Amnio CVS - methylation pattern may not yet be set in placenta Can get an un-interpretable result or a result that is not representative of the fetus
38
What are the considerations of testing an amnio for BWS?
Length of culturing time may affect methylation pattern High levels of mosaicism
39
How might balanced rearrangements cause BWS/RSS?
1. Positional effect: Maternally inherited translocation has 11p15 breakpoint - moves imprinting centre away from imprinted region --> abnormal IGF2 expression --> BWS 2. UPD: Maternal t(7;16) associated with maternal heterodisomy (mat UPD) due to 3:1 segregation and trisomy rescue --> RSS