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3:  Modes of inheritance and constitutional genetics > 12. BWS/RSS > Flashcards

12. BWS/RSS Flashcards

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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?

A

Up to 50%

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
Q

In a patient referred for BWS, what is the result of a CNV + methylation abberation on MS-MLPA?

A

Confirms BWS

Suggest array & parental testing to determine size of CNV & inheritance

High recurrence risk

26
Q

What are the two causes of RSS?

A

11p15 related

chr 7 related

27
Q

What is the chr 7 related cause of RSS?

A

Maternal UPD7

Approx 10% of cases

Heterodisomy and isodisomy, segmental UPD reported

28
Q

How is UPD7 tested for?

What genes are tested and why?

A

MS-MLPA

GRB10 and MEST both methylated on maternal allele - looking for gain of methylation

29
Q

What gene is tested for in UPD14? What is the methylation pattern?

A

MEG3

Methylated on paternal allele - loss of methylation = matUPD14

30
Q

What is paternal UPD14 associated with?

A

Kagami-Ogata syndrome

31
Q

What are the three 11p15 related causes of RSS?

Which is most common?

A

IC1 hypomethylation is most common (40-60%) - loss of methylation on paternal allele –> no IGF2 expression

Deletion/duplication at 11p15

Maternal UPD11

32
Q

What is the significance of UPD14?

A

Maternal UPD14 associated with Temple syndrome which has phenotypic overlap with RSS

33
Q

Which form of BWS is MLID associated with?

A

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
Q

What is MLID?

A

Multi locus imprinting disorder

Aberrant methylation at multiple imprinted loci across the genome

35
Q

Give an example of a disorder with a high proportion of MLID

A

Transient Neonatal Diabetes

Up to 60% of cases show MLID

36
Q

Why might BWS be indicated prenatally?

A

Exomphalos often detected in the first trimester scan

37
Q

What sample type is required for prenatal BWS testing & why?

A

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
Q

What are the considerations of testing an amnio for BWS?

A

Length of culturing time may affect methylation pattern

High levels of mosaicism

39
Q

How might balanced rearrangements cause BWS/RSS?

A
  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

3:  Modes of inheritance and constitutional genetics (19 decks)

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