Imprinting Disorders

Question 1

Typical methylation pattern for IC1 and IC2

Answer 1

typically IC1 is methylated on the paternally derived chromosome resulting in IGF2 expression (promotes cell growth and proliferation) and silencing of H19. On the maternally derived chromosome IC2 is methylated, resulting in silencing of KCNQ10T1 and expression of KCNQ1 and CDKN1C (negative regulator of cell proliferation)

Question 2

What are some common causes of Beckwith-Weidemann Syndrome?

Answer 2

• loss of methylation of IC2 on the maternal chromosome (50%)
• paternal uniparental disomy of 11p15.5 (20%)
• CDKN1C mutation (mat)
• Gain of methylation of the maternal IC1 site
• Paternal uniparental disomy
• unknown (20%)

Question 3

What are some causes of Russell-Silver Syndrome?

Answer 3

- Hypomethylation of the paternal IC1 site (35-50%)
- maternal uniparental disomy of chromosome 7 (7-10%)
- Microdeletion / Microduplication (mat) /
Translocations involving IC at 11p15.5
- Microdeletion / Microduplication / Mosaic
Trisomy 7
- Pathogenic variants in CDKN1C (mat), IGF2
(pat), PLAG1, or HMGA2
- Somatic maternal UPD11
- unknown (40%)

Question 4

What are the causes of Prader Willi Syndrome?

Answer 4

Happens when Dad’s copy is not expressed. Because Mom’s copy already is methylated normally. This can happen by:
- deletion of Dad’s copy of the gene
- maternal UPD (so all of Prader Willi genes are methylated/silenced)
- mutation of imprinting center or epimutation (both result in methylation of Dad’s copy)
- translocation: b/c it moves genes away from imprinting centers

maternal UPD can happen as trisomy 15 rescue event by deletion of dad’s

Question 5

What are the causes of Angelman Syndrome?

Answer 5

UBE3A on chromosome 15 is not expressed or translated into mRNA this can happen by:
- about 2 Mbp deletion on maternal chromosome 15 (ncludes region with UBE3A)
- UBE3A mutation in maternal copy
- maternal copy of chromosome 15 lost AKA paternal UPD
- methylation of maternal copy (imprinting defect)
Healthy:
paternal = UBE3 methylated
maternal = not methylated

Question 6

Explain how this inheritance apttern works.

Answer 6

The paternal copy of UBE3A is normally methylated, so if there is a mutation in UBE3A that is inherited from the father, the child will not be effected. This is because that mutation is silenced anyways. However, if a woman inherits the mutation in UBE3A this will be an issure for her children because the maternal allele of UBE3A is normally expressed, so if it is mutated it will not function properly and now there are no working copies of UBE3A.