Prenatal Diagnosis

Question 1

What percentage of neonates have a significant congenital abnormality?

Answer 1

2-3%

Question 2

When do you carry out prenatal diagnosis tests?

Answer 2

High risk i.e. family history of genetic disease, maternal illness (DM), previous history of an abnormal pregnancy
Or abnormal screening test

Question 3

What is screened for in a low risk pregnancy?

Answer 3

Major:
Congenital anomalies e.g. neural tube defects, congenital heart disease, brain malformations
Chromosome abnormalities

Question 4

What are the common neural tube defects?

Answer 4

Anencephaly and spina bifida (90%)
Open defects –> neural tissue and meninges exposed
Closed = 15-20%

Question 5

What is the test for neural tube defects?

Answer 5

Open: increased maternal serum alpha-fetoprotein
Closed: undetectable

Question 6

Why has there been a decline in neural tube defects?

Answer 6

Better nutrition and dietary folic acid

Question 7

What are the different types of chromosomal abnormality?

Answer 7

Aneuploidy = addition or loss of whole chromosome
Addition or loss of part of a chromosome
Chromosome rearrangement (translocation or inversion)

Question 8

How do you detect chromosome aneuploidies?

Answer 8

Cytogenetic analysis

Microarray analysis for addition or loss of part of a chromosome

Question 9

What are the common trisomies?

Answer 9

13, 18, 21, X
13 = Patau
18 = Edwards
21 = Down
XXY = Klinefelter

Question 10

What is Trisomy 21? Describe the symptoms

Answer 10

Down Syndrome
Intellectual disability - mild to moderate
Dysmorphic - nasal flat bridge, up slanting palpebral fissures, epicanthic folds (fold of skin on medial upper eyelid), single palmar crease, protruding tongue, clinodactyly (curvature of 5th finger towards adjacent 4th finger)
Cardiac defects - 40% of cases

Question 11

What is the incidence change of trisomy 21 with maternal age?

Answer 11

1:700 to 1:50 at maternal age 43

60% sponataneously abort

Question 12

What is Trisomy 18? Describe the symptoms.

Answer 12

Edward's syndrome
Severe learning disability
Dysmorphic - micrognathia, prominent occiput
Clenched overlapping fingers
Prominent heels and rocker-bottom feet
Cardiac defects

Question 13

What is the incidence change of trisomy 18 with maternal age?

Answer 13

1:3000 to 1:500 at age 43

30% die within 1 month, 90% one year

Question 14

What is Trisomy 13? Describe the symptoms

Answer 14

Patau Syndrome
Severe mental disability
Dysmorphic - cleft lip, cleft palate, holoprosencephaly, postaxial polydactyly, renal abnormalities, cardiac defects

Question 15

What is the prevalence change of trisomy 13 with maternal age?

Answer 15

1:5000 to 1:1100 at 43

45% die within 1 month, 85% within 1 year

Question 16

What is Turner Syndrome? What is the incidence?

Answer 16

1/5000

XO

Question 17

What is Klinefelter Syndrome? What is the incidence?

Answer 17

1/1000

XXY

Question 18

Describe the progression of prenatal ultrasound scanning?

Answer 18

Booking scan 1 trimester less than 15w
Foetal anomaly scan 18-20w second trimester. Most abnormalities pciked up here
Fetal MRI for brain imaging

Question 19

What is the early pregnancy scan for?

Answer 19

1. Establish gestational age accurately (essential for trisomy 21 screening)
2. Fetal crown-rump length <12 weeks or
3. Biparietal diameter >12 weeks.
4. Nuchal translucency measurements. Between 11-13w gestatation. Non-specific
   V few abnormalities picked up here
   Test of viability, foetal number and in multiple pregnancies the chorionicity/amnionicity
   Detection of gross fetal abnormalities.

Question 20

Which conditions is increased nuchal translucency thickness seen with?

Answer 20

Trisomy 21
Cardiac failure associated with congenital heart disease
Venous congestion in head and neck caused by constriction of foetal body (amniotic band, superior mediastinal compression caused by diaphragmatic hernia, narrow chest in skeletal dysplasia)
Abnormal development of the lymphatic system
Impaired fetal movement due to neuromuscular disorder
Foetal anaemia/hypoproteinaemia
Congenital infection through anemia or cardiac dysfunction
Some rare single gene disorders

Question 21

What is the normal nuchal thickness?

Answer 21

2.5mm

>5.5 = 80% risk adverse outcome (abnormality/fetal or postnatal death)

Question 22

From when are neural tube defects detectable by antenatal ultrasound? What are the signs?

Answer 22

Anencephaly 10-14 weeks
Spina bifida 16-22 weeks
Indirect cranial or cerebellar markers are Lemon + Banana signs - tonsils of the cerebellum come down onto spinal canal
Most detected by 20 week anomaly scan

Question 23

What is Meckel-Gruber syndrome?

Answer 23

Example of an abnormality that leads to specific diagnosis
Encephalocoele
6 digits
Single gene disorder

Question 24

What are the modes of screening?

Answer 24

Maternal age
Serum screening
Combined screening using information from ultrasound and maternal serum tests

Question 25

Describe alphafetoprotein

Answer 25

Reaches maternal serum directly across placenta or indirectly from amniotic fluid across chorion and amnion and then uptake by maternal vasculature in the decidua. Measure by immunoassay Levels change with gestation (lower trimester 2 than 1) Used to screen for NTDs and trisomy 21. Need accurate estimate of gestation at which sample is obtained to interpret Made by yolk sac and fetal liver

Question 26

What is the false positive problem in AFP serum tests?

Answer 26

Unaffected and spina bifida overlaps | At 5% false + rate around 75% open spina bifida cases detected. Balance between specificity and sensitivity.

Question 27

Why can you not use maternal age alone to screen for trisomy?

Answer 27

Because although risk rises, the majority of cases still occur in younger women

Question 28

What are the prenatal markers for Down Syndrome?

Answer 28

Maternal age Nuchal scan Brackets = multiple of median Serum screening for AFP (0.75), unconjugated estriol (0.73), hCG (2/05) If greater than 1 in 250 threshold risk, i.e. 5% false positive rate, give women amniocentesis

Question 29

Give examples of tests used in high risk pregnancies

Answer 29

``` Invasive CVS chorionic villus sampling Amniocentesis Fetal blood sampling Non-invasive Ultrasound Free fetal DNA ```

Question 30

Describe CVS

Answer 30

Chorionic villus sampling Enables samples to be taken in first trimester after 11 weeks Fetally derived cells (trophoblast) Maternal material must be discarded Gives good preparations of DNA without culture Chromosome analysis can be done rapidly within 24h, but best quality analysis after 2 weeks culture. 1-2% miscarriage risk. Possible of surgical termination in 1 trimester. Problem: testing placenta not fetus - some abnormalities are seen in the placenta but not the fetus so diagnositclaly difficult

Question 31

Describe amniocentesis

Answer 31

10-20 mls of amniotic fluid sampled transabdominally under US 16w gestation or later Cells from amnion, fetal skin and urinary tract pelleted Culture 2 weeks Longer culture may be needed for DNA or biochemical studies - nb rapid trisomy screen results by PCR bypass this time requirement 0.5% risk miscarriage Medical/late termination of pregnancy.

Question 32

What are the pros and cons of CVS?

Answer 32

``` Pro Earlier Diagnosis Cons Higher risk miscarriage Extraembronic tissue Possibility of confined placental mosaicism ```

Question 33

What are the pros and cons of amniocentesis?

Answer 33

``` Pros Fetal material Lower risk miscarriage Cons Later diagnosis ```

Question 34

How do you investigate fetal structural anomaly?

Answer 34

Karyotype - misses inversions and translocations Chromosomal microarrays +5% DNA sequencing + ??%

Question 35

What is a foetoscopy and what is it used for

Answer 35

Foetal skin biopsy | Used for hereditary skin disorders e.g. epidermolysis bullosa

Question 36

What is cordocentesis and what is it used for?

Answer 36

Foetal blood sampling for chromosomal disorders, haematological disorders and congenital infection

Question 37

What is the total schema of Pre-implantanation genetic diagnosis?

Answer 37

1. Genetically examine couple 2. Genetic conclusion 3. Fertilisation IVF or ICSI 4. Blastomer biopsy 5. PCR FISH 6. Embryo transfer (not more than 2)

Question 38

What are the pros and cons of cell free foetal DNA?

Answer 38

No increased risk miscarriage Easier sample collection Earlier diagnoses (from 7 weeks)

Question 39

Describe cell free fetal DNA testing cffDNA

Answer 39

Originates from placenta Represents whole fetal genome Detectable from 4 weeks % increases with gestation 10-20% total cfDNA Cleared from circulation within 30 mins delivery Shorter than maternal cfDNA 166bp cw 143 bp

Question 40

What is NIPD NIPT NIPS?

Answer 40

Non invasive prenatal diagnosis/testing/screening NIPD for high risk cases - doesn't require invasive test for confirmation ie single gene disorders, sex determination NIPT NIPS for low risk cases. Aneuploidy. Requires invasive testing for confirmation.

Question 41

Give examples of use of NIPD

Answer 41

Fetal sex determination genes on Y chromosome - don't need to test female.