Genetics

Question 1

What do you need to do a DNA or chromosome test on a baby in utero?

Answer 1

Tissue with the same genetic make up

Question 2

What are some examples of foetal testing?

Answer 2

Placenta- chorionic villus biopsy
Skin/Urine cells- amniocentesis
Blood- foetal blood sampling
Foetal DNA from maternal serum

Question 3

When can CVS be carried out?

Answer 3

11.5 weeks

Question 4

When can amniocentesis be carried out?

Answer 4

15 weeks +

Question 5

What is the miscarriage risk of CVS?

Answer 5

1-2%

Question 6

What is the miscarriage risk of amniocentesis?

Answer 6

0.5-1%

Question 7

What is the miscarriage risk of foetal blood sampling?

Answer 7

1-2%

Question 8

What is the miscarriage risk of foetal DNA from maternal blood?

Answer 8

None

Question 9

When can foetal DNA from maternal blood be tested?

Answer 9

8 weeks +

Question 10

When can foetal blood sampling be carried out?

Answer 10

18 weeks +

Question 11

What viability of tissue is needed in CVS?

Answer 11

Good

Question 12

What viability of tissue is needed in amniocentesis?

Answer 12

Poor

Question 13

What viability of tissue is needed in foetal blood sampling?

Answer 13

Good

Question 14

What viability of tissue is needed in foetal DNA from maternal blood testing?

Answer 14

Stable mother

Question 15

What risks are there in CVS?

Answer 15

Miscarriage

Confined placental mosaicism

Question 16

What limits are there in foetal DNA from maternal blood testing?

Answer 16

Limited analyses available

Question 17

What whole genome analyses are available?

Answer 17

Standard karyotype- in metaphase
Array CGH (chromosomes)
Quantification of foetal DNA in maternal serum
Whole genome sequencing

Question 18

What targeted analyses are available?

Answer 18

Point mutation testing
FISH
Quantitative Fluorescent PCR

Question 19

What are copy number variations?

Answer 19

Insertions or deletions of DNA segments

Question 20

How can you tell if a change is a copy number variation or mutation?

Answer 20

Mutation will be de-novo, polymorphism will be present in normal parent
Mutation will be bigger, affect known gene, and previously reported in same phenotype

Question 21

When is FISH used?

Answer 21

When missing chromosome is too small to see

Question 22

What is QF PCR used for?

Answer 22

Rapid counting of specific chromosomes- allows a dosage analysis of polymorphic repeat sequences at several loci on target chromosomes

Question 23

When is aCGH or chromosome analysis used?

Answer 23

High risk of chromosomal trisomy on screening
Fetal abnormality on scanning-small size, especially if symmetrical growth failure, increased nuchal thickness, structural malformation e.g. brain, heart
Parent has balanced chromosomal rearrangement

Question 24

When is serum screening carried out?

Answer 24

Week 16- look for biochemical markers of Down’s

Question 25

When is a detailed scan to look for other fetal abnormalities carried out?

Answer 25

20 weeks

Question 26

When may increased nuchal thickness be seen?

Answer 26

Dating USS at 12 weeks

Question 27

What can be assessed through free fetal DNA in maternal circulation?

Answer 27

Sex determination Trisomy testing Chromosome deletions Single gene

Question 28

Why is free fetal DNA in maternal circulation a challenging test?

Answer 28

Only 10% of DNA comes from fetus

Question 29

If a pregnant women who has 1 son with DMD, what test should be carried out?

Answer 29

NIPT through free fetal DNA to look for Y chromosome, if found do CVS

Question 30

A pregnant women of 18 weeks has a detailed scan showing an AVSD, a common defect in Down's, what testing should be done and why?

Answer 30

Amniocentesis/aCGH 18 weeks Cardiac defect may have other causes aCGH will detect small deletions such as 22q11

Question 31

From initial 18 week scan and detection of AVSD on USS, when should amnio and aCGH be performed and results confirmed by?

Answer 31

+1-2 days: amniocentesis | +6 days: aCGH confirms result

Question 32

What is a Robertsonian translocation?

Answer 32

Two acrocentric chromosomes stuck end to end (increased risk of trisomy)

Question 33

What is aneuploidy?

Answer 33

Too many or too few chromosomes

Question 34

What would aCGH look like in the parent with a balanced translocation ?

Answer 34

Normal- aCGH only detects imbalance

Question 35

What reproductive risks are there in reciprocal translocations?

Answer 35

For most translocations, ~50% will have either normal chromosomes or balanced translocation Unbalanced: Miscarriage (large segments) Dysmorphic delayed child (small segments)

Question 36

A 10wks pregnant woman comes to see you, she has a balanced reciprocal translocation between Ch4 and Ch9, known to have a high risk of multiple malformations in a liveborn child, how do you manage?

Answer 36

CVB at 11.5 weeks Direct Karyotype or Fish may be available at 11.5+3 days At 13 weeks full karyotype complete

Question 37

What is aCGH used for?

Answer 37

Chromosome deletions/duplications (analysis for balanced rearrangements)

Question 38

What needs to be known to use FISH or DNA analysis?

Answer 38

Diagnosis

Question 39

When can specific anomalies be detected?

Answer 39

Cardiac 12-20wks Microcephaly after 22wks Short Limbs after 22wks Brain malformations

Question 40

What is the best management to test for suspected DMD?

Answer 40

CVB

Question 41

How can free fetal DNA in maternal serum help in diagnosing DMD?

Answer 41

At 8 weeks sexing on DNA, if boy proceed to invasive testing, if girl no concerns

Question 42

What is Pre Implantation Genetic Diagnosis (PGD)?

Answer 42

Perform a genetic test on an embryo before re-implanting one with the 'correct' genotype

Question 43

What is the process involved in PGD?

Answer 43

``` Down regulation Ovarian stimulation- FSH USS-follicular assessment Oocyte retrieval Fertilisation by ICSI Embryo biopsy day 3 ```

Question 44

When may PGD be considered?

Answer 44

``` Parental chromosome abnormality Robertsonian translocation Reciprocal translocation X-linked disorders Re-implantation of female embryos Other single gene disorders Increasing numbers of conditions Spinal Muscular Atrophy Cystic fibrosis Huntingtons disease ```