12. BWS/RSS

Question 1

What is the result of DNA methylation?

Answer 1

Repressing/silencing transcription

Question 2

Which residues can be methylated? What is the mechanism?

Answer 2

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

Methly group added to cytosine residue to produced 5-methylcytosine

Question 3

What is the definition of imprinting?

Answer 3

Genes that are differentially methylated depending on their parent of origin

Leads to monallelic, parent-specific gene expression

Question 4

When are imprinting patterns erased?

Answer 4

During the development of the parental gametes for transmission to offspring

Question 5

What is the BWS/RSS critical region?

Answer 5

11p15

Question 6

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

Answer 6

IC1/H19DMR - IFG1 & H19

IC2/KvDMR - CDKN1C, KCNQ1, KCNQ1OT1

Question 7

Describe the methylation pattern of IC1/H19DMR

Answer 7

IC1 methylated on paternal chromosome, unmethylated on maternal chromosome

Paternal chr - H19 suppressed, IGF2 expressed

Maternal chr - H19 expressed, IGF2 suppressed

Question 8

What is the role of IFG2 and H19?

Answer 8

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

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

Question 9

Describe the methylation pattern of IC2/KvDMR

Answer 9

IC2 unmethylated on paternal chromosome, methylated on maternal chromosome

Paternal chr - KCNQ1OT1 expressed, KCNQ1 & CDKN1C suppressed

Maternal chr - KCNQOT1 suppressed, KCNQ1 & CDKN1C expressed

Question 10

What is the role of CDKN1C and KCNQ1?

Answer 10

CDKN1C - regulates prenatal and postnatal growth and development

KCNQ1 - potassium channel

Question 11

What proportion of BWS cases are sporadic vs inherited?

Answer 11

85% sporadic, 15% inherited (AD)

Question 12

What is the predominant cause of sporadic BWS?

Answer 12

Loss of methylation (hypomethylation) at maternal IC2/kvDMR

Causes loss of CDKN1C and KCNQ1 expression + increased expression of KNCQ1OT1

Question 13

What is associated with some BWS cases and caused by loss of methylation at maternal IC2/kvDMR?

Answer 13

Multilocus imprinting disorder (MLID) in 33% of cases

Aberrant methylation at other imprinted loci across the genome

Usually no added clinical features from having aberrant methylation at other loci

Question 14

What is the second most common cause of sporadic BWS?

What does it result in?

Answer 14

Paternal UPD11p15

Hypermethylation of IC1 AND hypomethylation of IC2

Question 15

Why is paternal UPD11p15 always mosaic?

What is the exception to this?

Answer 15

Post zygotic event caused by recombination errors in mitosis in early development

Exception is if there is a pre-disposing chr rearrangement

Question 16

What is the third most common cause of sporadic BWS?

Answer 16

Gain of methylation (hypermethylation) at maternal IC1/H19DMR

Causes loss of H19 expression + increased expression of IGF2

Question 17

Why do mutations in CTCF binding sites result in BWS?

Answer 17

Cause paternal pattern of DNA looping on both chromosomes - IGF2 is expressed biallelically

Question 18

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

Answer 18

Up to 50%

Question 19

What are the 2 main causes of BWS, other than hypomethylation of maternal IC2, hypermethylation of maternal IC1, and paternal UPD?

Answer 19

1. Maternal CDKN1C point mutations
2. Duplications (paternal) and deletions at 11p15 - must have an accompanying methylation change

Question 20

What is the role of CDKN1C?

Answer 20

Inhibits cyclin/cyclin-dependent complexes of the G1 phase - negative regulator of cell proliferation

Expressed from maternal allele - loss results in overgrowth

Mutations in maternally inherited allele cause BWS

Question 21

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

Answer 21

CDKN1C testing

Pathogenic variants have high recurrence risk

Question 22

When is SNP array required?

Answer 22

1. GOM at IC1 and LOM at IC2 - suggestive of pat UPD11, array to confirm
2. Borderline methylation result for IC1 and IC2 - ?pat UPD11
3. Normal MS-MLPA, array to exclude low level UPD11

Question 23

What is the result of a CNV + methylation abberation?

Answer 23

Confirms BWS

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

High recurrence risk

Question 24

What are the clinical features of BWS?

Answer 24

Macroglossia, exomphalos, hemihyperplasia, Wilms tumour/nephroblastoma, macrosomia, prolonged hyperinsulinism

Question 25

What are the clinical features of RSS?

Answer 25

Low birth weight, short stature, characteristic triangular facies, body asymmetry

Question 26

What are the two causes of RSS?

Answer 26

11p15 related

chr 7 related

Question 27

What are the three 11p15 related causes of RSS?

Which is most common?

Answer 27

IC1 hypomethylation is most common (40-60%) - loss of methylation on paternal allele

Deletion/duplication at 11p15

Maternal UPD11

Question 28

What is the chr 7 related causes of RSS?

Answer 28

Maternal UPD7

Heterodisomy and isodisomy, segmental UPD reproted

Question 29

How is UPD7 tested for?

What genes are tested and why?

Answer 29

MS-MLPA

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

Question 30

What is MLID?

Answer 30

Multi locus imprinting disorder

Aberrant methylation at multiple imprinted loci