Imprinting Disorders

Question 1

What are the two most common mechanisms leading to BWS?

Answer 1

-Maternal loss of methylation at the ICR2 region (50% of cases) leads to reduced CDKN1C, so too much IGF2
-Paternal UPD of 11p15.5 (20% of cases).

Question 2

Which genes is most commonly affected in BWS, and what is its role?

Answer 2

CDKN1C: regulates cell growth; loss of function due to mutations or methylation changes contributes to overgrowth phenotypes.
IGF2: A growth-promoting factor overexpressed in paternal UPD.
H19: A non-coding RNA that suppresses IGF2; reduced expression leads to growth dysregulation.

Question 3

What is the recommended testing cascade for suspected BWS?

Answer 3

Cascades
1) Methylation (MS-PCR) first then if:
2a) positive do Deletion Testing (KT, FISH, Array)
2a.i) Yes deletion ->CMA to detect size
2a.ii) No deletion ->UPD analysis with array.
2b) if at any point in cascade you get a null result (eg negative methylation no upd, positive methylation but negative deletion and no upd etc) then->seq/del/dup IC1/2 )

Bottom line think of frequency and test accordingly: methylation +/-Fish/KT), UPD then sequence

Question 4

What are the cardinal clinical features of BWS?

Answer 4

1)Macroglossia (enlarged tongue).
2)Omphalocele or other abdominal wall defects.
3)Hemihyperplasia (asymmetric overgrowth of body parts).
4)Neonatal hypoglycemia.
5)Increased risk for embryonal tumors, such as Wilms tumor BUT not for the most common type (maternal hypo of IC2)

Question 5

How does the cancer risk differ in BWS patients with different genetic changes?

Answer 5

-Maternal hypomethylation at ICR2, leads to low CDKN21C so too much IGF2: Low cancer risk.
-Hypomethylation at ICR1 or paternal UPD11p15: High cancer risk, particularly for Wilms tumor and hepatoblastoma.

Question 6

What mechanism in BWS makes it appear as though the syndrome “skips” generations and what sex needs to pass this mechanism along for it to appear

Answer 6

maternal hypomethylation at ICR1 means H19 is down and IGF2 turned up so more IGF2 then CDKN1C even though its being made as usual. BUT if a dad passes this to male or female child it wont manifest it only shows up when the female carrier has a kid

Question 7

What are the two most common mechanisms leading to SRS?

Answer 7

-hypomethylation of ICR1 region at 11p15.5 on the paternal allele (35–50% of cases) -> reduces IGF2 expression, impairing growth.
Maternal UPD of chromosome 7 (7–10% of cases).

Question 8

Which genes are most commonly involved in SRS, and what are their roles?

Answer 8

IGF2: Reduced expression due to hypomethylation at ICR1, impairing growth.
GRB10: Overexpression on chromosome 7 in cases of maternal UPD, contributing to growth restriction.

Question 9

What are the hallmark clinical features of SRS?

Answer 9

-IUGR and postnatal growth failure.
-Relative macrocephaly: Head size is preserved relative to body size.
-Triangular facies: Small chin and narrow face.
-Body asymmetry: Hemihypertrophy or leg-length discrepancy.
-Feeding difficulties and failure to thrive in infancy.