Week 3 - F - Antenatal Genetics 1 - array cgh, non invasive prenatal testing, amniocentesis and chorionic villus sampling

Question 1

Clinical geneticist are sometimes required in pregnancy - here are some examples of when: Where there is a family history of disease that may affect the pregnancy (fetus or mother) Where there is an unexpected finding in pregnancy

• * Genetic testing
• * Ultrasound scanning

Where a previous pregnancy/child has malformations

• What are the ways to test a babies DNA ?

Answer 1

Placenta - Chorionic vilus sampling

Skin/urine cells - Amniocentesis

Blood - fetal blood sampling

Question 2

When can amniocentessis and chorionic villus sampling be carried out? What are the miscarriage rates associated with each of these?

Answer 2

Amniocentesis - usually carried out after 15 weeks gestation - 1% miscarriage rate Chorionic villus sampling - usuallycarried out after 12 weeks gestation (between 11 and 14 weeks) - miscarriage rate of 2%

Question 3

What is the risk of carrying out amniocentesis before 15 weeks of pregnancy?

Answer 3

The risk of carrying out amniocentesis before 15 weeks gestation is the baby developing clubfoot (Talipes equinovarus)

Question 4

Why is there poor viability of tissue when carrying out amniocentesis?

Answer 4

This is because amniocentesis essentially collects any cells shedded by the foetus eg urine or skin cells

Question 5

In most pregnancies the chromosomal complement detected in the fetus is also present in the placenta. The detection of an identical chromosomal complement in both the fetus and its placenta has always been expected as both develop from the same zygote What can chorionic villus sampling detect? It usually requires amniocentesis also to show that the foetal cells are different

Answer 5

CPM (confined placental mosaicism) is diagnosed when some trisomic cells are detected on chorionic villus sampling and only normal cells are found on a subsequent prenatal test, such as amniocentesis or fetal blood sampling. CHorionic villus sampling can show confined placental mosaicim

Question 6

What can having confined placental mosacism cause for miscarriage rates after chorionic villus sampling?

Answer 6

The msicarriage rates in mothers with confined placental mosacisim when carrying out chorionic villus sampling are higher than in those with confined palcental mosacism

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Question 7

Array-Comparative Genomic Hybridisation is essentially just a clever way at looking at chromosomes How does Array CGH work?

Answer 7

It essentially counts the number of chromsomes and can therefore spot chromsomal imbalances

Question 8

What can be used in the diagnosis of Prader Willi syndrome?

Answer 8

Can use Array CGH or FISH - fluorescence in situ-hybridisation - can be used Prader Willi is most commonly caused by a microdeletion on paternal chromsome 15

Question 9

What is the difference between a polymorphism and a mutation?

Answer 9

A polymoprhism is when there is a genetic variation that is not per-se disease causing Mutation can be defined as a genetic change that causes disease

Question 10

Recall When can amniocentesis be carried out from? When can chorionic villus sampling be carried out from? When can foetal blood smapling be carried out from?

Answer 10

Amniocentesis - carried out from after 15 weeks gestation (so 16 weeks onwards) Chorionic villus sampling - carried out from 11 weeks onwards Foetal blood sampling can be carried out from 18 weeks + gestation

Question 11

When the missing part of chromsome is too small to see on array cgh, what can be used? This test can only be used when targeting a specific area and will not target the whole genome

Answer 11

FISH - flouresence in-situ hybridisation

Question 12

When is array CGH or chromosome analysis carried out?

Answer 12

Carried out if there is a high risk of trisomy on screening Foetal abnormality on scan Or parent has a chromsomal abnormality

Question 13

When is the booking visit ultrasound scan taken in the female? When is the other ultrasound scan taken?

Answer 13

Booking ultrasound scan is taken at around 12 weeks of gestation The second ultrasound scan is taken at around 20 weeks of gestation

Question 14

What is looked for as a sign of downs in the 1st ultrasound scan?

Answer 14

Look for the nuchal thickness in the pregnancy - greater thickness increases the risk of down’s syndrome

Question 15

What can be used as an extra for screening for downs in the first semester? Nuchal thickness in combination with these is known as the combined test

Answer 15

* Nuchal thickness - increased in a child with DOwns * Free-bHCG - raised in a child with downs * PAPP-A - pregnancy associated plasma protein A - decreased in a child with downs

Question 16

If the mother books in late and therefore the ultrasound scan measuring nuchal thickness is not as viable, a quadruple test screening for downs can be carried out What is measured in the quadruple test? When can this serum test be carried out?

Answer 16

Quadruple test Carried out from 15 - 20 weeks gestation Measures Alfa-foeta protein Unconjugated estradiol Free or total b-HCG INhibin A

Question 17

Why is it that measuring foetal DNA from maternal circulation is not commonly done? - this is known as non-invasive prenatal testing (or cell-free DNA (cfDNA) screening )

Answer 17

Only 10% of DNA comes from fetus, the rest is maternal and it is therefore difficult to collect enough cell-free DNA (cfDNA) from the blood sample

Question 18

Non-Invasive Prenatal Testing (NIPT) for Down’s syndrome For many years the goal of researchers has been to develop a diagnostic prenatal test for Down’s syndrome that does not involve an invasive procedure with an accompanying risk of miscarriage. The most recent breakthroughs have involved analysing cell-free maternal and fetal DNA in the mother’s blood. This has come to be known as ‘non-invasive prenatal testing’ (NIPT), because all that is needed is a maternal blood test. If there is a high risk of downs, what can be carried out?

Answer 18

If there is a high risk of Down’s associated with Non-invasive prenatal testing, chorionic villus sampling or amniocentesis can be carried out

Question 19

Non-invasive prenatal testing is currently not available in the NHS (2017) What week of gestation can testing foetal dna from maternal blood be carried out?

Answer 19

Testing foetal DNA from maternal blood can be carried out from 8 weeks of gestation

Question 20

Mrs Pink comes to see you. She is 10 weeks pregnant. She has a son who is affected with Duchenne muscular dystrophy. NIPT (Non invasive prenatal testing) can help take the foetal DNA to determine the sex of the baby and therefore see if further tests are requried (results take 10 days to 14 to come back with NIPT) If NIPT says that the child is male, what test can be carried out?

Answer 20

Chorionic villus sampling can be carried out in this mother as she will be roughly 12 weeks pregnant when results come through and therefore can look for mutations

Question 21

Mrs Green is 12 weeks pregnant – serum biochemistry and nuchal thickness measurement gives a risk of 1 in 40 that the baby is affected with Down syndrome What was measured in the serum biochemsitry? A risk greater than what, warrants further investigation for Down’s syndrome?

Answer 21

IN the serum biochemistry Free-bHCG was measured and PAPP-A (Pregnancy associated plasma protein A) was measured A risk greater than 1in150 warrants further investigation

Question 22

Mrs Green is 12 weeks pregnant – serum biochemistry and nuchal thickness measurement gives a risk of 1 in 40 that the baby is affected with Down syndrome What test can be carried out?

Answer 22

Carry out Chroionic villus sampling to obtain DNA of foetus - 2% miscarriage rate

Question 23

Mrs Blue comes to see you. She is 18 weeks pregnant. A detailed scan has shown that her baby has a cardiac defect: an AtrioVentricular Septal Defect (AVSD) that is commonly seen in Down syndrome. What is your best ‘genetic’ management? 1. Reassurance 2. Serum Screening 3. Chorionic Villus Biopsy 4. Amniocentesis 5. Non-Invasive Prenatal testing

Answer 23

4 - Amniocentesis would be best - 18 weeks of age

Question 24

What is the best genetic test to carry out for the previous case once amniocentesis has collected sample and why? 1. Array CGH 2. Karyotype 3. Chromosome analysis 4. FISH for 21 5. DNA testing for a point mutation

Answer 24

1 - Array CGH

Cardiac defect may be downs but it could also be caused by a different genetic mutation which the array-cgh would be able to detect

Question 25

Write the karyotype for person? What condition is this?

Answer 25

45 XY t(14,21)

This is a type of Down’s syndrome - robertsonian translocation downs

Question 26

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Answer 26

aCGH would appear normal as it only detects chromsomal imbalances

Question 27

Mrs Roberts comes to see you. She is 10 weeks pregnant. She has a balanced reciprocal translocation between chromosome 4 and chromosome 9, that has a high risk of causing a liveborn child with multiple malformations. What is the best investigation?

Answer 27

Since it is at 10 weeks - best to carry out Chorionic villus biopsy when 11.5 weeks reached as is early stage of pregnancy