14. Prenatal mosaicism

Question 1

Why does mosaicism detected prenatally complicate counselling?

Answer 1

Due to variability in phenotypic outcome

Question 2

What are the 3 types of mosaicism that must be distinguished?

Answer 2

True constitutional mosaicism

Confined placental mosaicism

Pseudomosaicism - chr abn. in <2% of cells, often technical artefact of culturing

Question 3

Why is mosaicism detected in a higher proportion of CVSs than AFs?

Answer 3

1. Some pregnancies lost between CVS and amnio
2. Mosaicism often found in placenta, only detected by CVS

Question 4

What are the two ways in which mosaicism occurs?

Answer 4

1. Mitotic non-disjunction in zygote
2. Meiotic non-disjunction in gamete, followed by anaphase lag/trisomy rescue in mitosis

Question 5

What risk is associated with trisomy rescue?

Answer 5

UPD - leaves 2 homologs derived from the same parent

Question 6

What are the 2 cell populations of the blastocyst?

What do they form?

Answer 6

1. Trophoblast - forms chorion (extra embryonic tissue)
2. Inner cell mass - forms amnion and embryo

Question 7

What 3 cell populations does the inner cell mass form?

Answer 7

1. Epiblast (ectoderm)
2. Hypoblast (endoderm)
3. Mesoderm forms between epiblast and hypoblast

Question 8

What sort of error occurs in trophoblast/chorion and why?

Answer 8

Mitotic errors (i.e. non-disjunction)

Chorion branches off in early development and divides rapidly

Question 9

What are the 2 levels of pseudomosaicism?

Answer 9

Level 1 = single abn cell in single culture

Level 2 = > 2 abn cells derived from same culture

Question 10

What is level 3 mosaicism?

Answer 10

> 2 abn cells across >2 colonies/suspensions

Question 11

When might pseudomosiacism be reported and followed up, and how?

Answer 11

Level 2 for a clinically significant aneuploidy

Recommend follow up with AF if found on CVS to exclude CPM

Question 12

What further studies would be required following detection of level 3 mosaicism in a CVS?

Answer 12

Follow up with amnio - mosaicism present = true constitutional, absent = CPM

If CPM - DNA studies if imprinted chr is involved (6, 7, 11, 14, 15, 20) due to risk of UPD due to trisomy rescue

High resolution USS

Question 13

What trisomies are commonly observed in CPM, and what is their origin?

Answer 13

2, 3, 7, 8 - mitotically derived

16, 22 - meiotically derived

Question 14

Other than UPD, what risk is associated with meiotically derived CPM?

Answer 14

CPM for T16 and T22 may cause placental dysfunction leading to IUGR

Question 15

What causes Pallister-Killian syndrome?

Answer 15

Mosaic supernumerary isochromosome 12p (tetrasomy 12p)

Abn cells in fibroblasts, AF, CVS, BM but not in dividing lymphocytes

Question 16

What is an isochromosome?

Answer 16

Unbalanced structural rearrangement with 2 copies of the same arm

Question 17

Why is iso12p absent from blood?

Answer 17

Instability of i12p at mitosis and high turnover rate of lymphocytes

Question 18

Which mosaic trisomies have the highest risk of abn outcome?

Answer 18

2, 4, 9, 16, 22

Question 19

How are all prenatally diagnosed mosaic trisomies followed up?

Answer 19

High resolution ultrasound

Question 20

What is the most common cause of CPM and why?

Answer 20

Mitotically derived CPM

Placental cells divide rapidly so are susceptibly to mitotic errors

Question 21

What is a CVS? What is it composed of?

Answer 21

Chorionic villi are part of placental tissue

Composed of cytotrophoblast and mesenchyme core

Question 22

What is confined placental mosaicism?

Answer 22

Presence of abnormal cells in in extraembryonic tissues (placenta), not in fetus

Question 23

What cell types is CPM found in?

How often is CPM found?

Answer 23

50% trophoblasts
30% mesenchyme
20% both

Found in 1-2% of pregnancies at 10-12 weeks

Question 24

How does the location of CPM relate to the cause?

Answer 24

CPM in trophoblasts or mesenchyme = mitotic non-disjunction

CPM in both trophoblasts and mesenchyme = Trisomy rescue following meiotic non-disjunction

Question 25

Which cells in a CVS are most representative of the fetal karyotype?

Answer 25

Mesenchyme core - has similar embryological origin

Question 26

What is the significance of identifying a trisomy in a CVS but not an AF/fetal blood?

Answer 26

CPM, risk that it was caused by trisomy rescue - therefore risk of UPD