Marker Chromosomes At PND

Question 1

sSMC definition?

Answer 1

sSMC are structurally abnormal chromosomes that can’t be identified unambiguously by conventional banding alone, & are equal in size or smaller than chr 20 of same metaphase spread.

Question 2

What is prevalence of market chromosomes in prenatal setting?

Answer 2

• ~1/1,000 cases G&S

- Lier et al 2007: 0.075% in unselect Ed referrals & 0.204% in ultrasound abnormalities!

Question 3

What are marker characterisation guidelines?

Answer 3

• Routine cyto methods should be used as far as possible:
  C-banding: establish the presence/absence of C+be heyerochromatin & C-be euchromatin.
  In general, C band +be markersconposed entirely of heterochromatin are considered of less risk as there is little active genetic content.
  C-Banding: establish the number of centromeres present allowing marker to be characterised as ducentric of monocentric!

Silver Staining: will establish presence of satellite structures: narrowing down chr of origin to 13, 14, 15, 21, 22!

CONCURRENTLY:

(1) . Ask for parental bloods: investigate inheritance. Generally, inherited marker chromosomes are less likely to be significant than de novo markets (BUT levels of mosaicism & tissue distribution may have different effects indifferent individuals).
(2) . Extract DNA for possible UPD studies IF market derived from known imprinted chromosome.
(3) . FISH testing should be performed until marker origin established):
- ~80% markers are chr 15 derived & chr 15 probes as well at 13/21, 14/22 (whether satellites present or not).
- if satellites are not present, then X & Y FISH.
- Probes for chr conferring risk of UPD (ie. 7,11,14,15).
- Once origin identifies, whole ch paints & other FISH probes should be considered.
- Guideline old, now should consider using arrays!!

Question 4

Further studies once marker identification established.

Answer 4

• Chr 15 markers require further tests to distinguish between largely benign SMALL inv dup(15) & larger pathogenic inv dup(15) which contains SNRPN gene in the PW/AS region characterised by Mental retardation, epilepsy & autism.
• Chr 22 tests to determine whether euchromatin present & involvement of cat eye syndrome!
• i(12p), i(18p), i(18q) markets generally identified by g banding alone.
• UPD studies: should be considered if imprinted chromosome involved; particularly Chr 15. Marker Chr May be result of an imperfect trisomy rescue event.
• Sex Chr derived markers: Presence or absence of XIST should be investigated for X derived markers.

Question 5

Clinical Significance of marker chromosomes?

Answer 5

• Warburton 1991: Overall risk of an abnormality associated with presence of marker Chr at prenatal diagnosis is 13%!
• Graf 2006 7% risk derived from Chr 13,14,2,22
• Graf 2006: non-Afrocentric Chr the risk is 28%, which drops to 18%with normal scan.
• 15 derived markers: if contain PWS/AS region, carry’s High risk for abnormality! MR, epilepsy, autism & possible dysmorphism). UPD must also be considered.
• 22 derived may show features of cat eye syndrome, depending on amount of euchromatin present.
• 14 derived, generally low risk. UPD must also be considered.
• 13/21 derived, low risk but dependant on material they contain.
• Metacentric markers incl i(12p), i(18p), i(18q), are assoc with high risk of abnormality.
• Eing marker Chr May be assoc with an increased risk compared to non ring due to instability at meiosis & May manifest features of ring syndrome!!
• X markers: Small X markers lacking XIST usually worse phenotype due to lack of X inactivation of the small marker, resulting in functional display for part of X. Markers containing XIST are usually inactivated!!!
• Presence of euchromatin confers increased risk compared with heterochromatin.