7. Prenatal Screening

Question 1

How many babies are born/year

Answer 1

70,000

Question 2

What percentage of babies have birth defects

Answer 2

4%

Question 3

What kind of birth defects exist?

Answer 3

Structural Functional Genetic Chromosomal Biochemical

Question 4

What is the most common chromosomal abnormality?

Answer 4

Trisomy 21 (1 in 600 ~ 1 in 1000) 2nd most common XXY (Klinefelter syndrome)

Question 5

What information is important from taking a family history?

Answer 5

• Should ask a 3 generation family history Including age of diagnosis

Question 6

What questions should you ask when taking family history?

Answer 6

• Inherited conditions - Down syndrome and other chromosomal conditions - Other birth defects, e.g. spina bifida, cleft/lip palate, cardiac defects, intellectual disability - Recurrent miscarriage - Unexplained perinatal deaths - Consanguinity - Ethnic background - IVF/Donor gametes

Question 7

What is the risk of giving birth to a child with Down Syndrome?

Answer 7

Increases exponentially from 1 in 1411 at age 20-24 to 1 in 32 at age 45

Question 8

What is the prevalence of neural tube defect?

Answer 8

1 in 500 o Spina bifida o Anencephaly o Encephalocele - Folate Should be taken before and during pregnancy

Question 9

What are the benefits of prenatal testing?

Answer 9

• Offers reproductive choice - Risk information - Choice of termination - Prepare psychologically - Help plan delivery and management - Provide reassurance

Question 10

What are the 2 major types of prenatal testing?

Answer 10

Screening test - Offered to all pregnant women - Non-invasive - Taken by up to 80% pregnant women Diagnostic tests - Offered to women who are at increased risk of having a child with a birth defect - Invasive

Question 11

What is the 1st trimester combined screening?

Answer 11

• Blood taken at 10 weeks o 2 biochemical analytes measured - Ultrasound performed at 11 -13 weeks. o Nuchal translucency measured (oedema that occurs behind fetal neck) o Crown rump length (dating) - Other factos including maternal age Results/Cutoff - T21: 1 in 300 - T18: 1 in 175 Detection rate for T21 is 93% - 4.6% false positive result

Question 12

What is the 2nd trimester combined screening?

Answer 12

• Blood taken at 14-20 weeks (15-17 ideal) o 4 biochemical analytes measured - Maternal age Cutoff - T21 1 in 250 - T18 1 in 200 - Neural tube defects >2.0MoM Detection rate for T21 is 85%, with 6.5 false positive rate Detection rate for neural tube is 93% but ultrasound is recommended

Question 13

What is NIPT/S?

Answer 13

(non-invasive prenatal testing/screening) – using Cell-free fetal DNA/RNA in maternal blood - Non invasive - ~10 weeks gestation - Uses new sequencing technology

Question 14

What does Chronic cillus sampling (CVS) involve?

Answer 14

• From 11 weeks gestation - Placental tissue - Ultrasound - Invasive 1% miscarriage - If termination of pregnancy requested, dilation & curettage under general anaesthetic (

Question 15

What is Amniocentesis?

Answer 15

15-16 weeks gestation

Amniotic fluid (20ml) containing sloughed off fetal cells removed

Ultrasound

0.5% miscarriage

If TOP requested, by prostaglandin (>16 wks)

Question 16

What is fish?

Answer 16

• Fluorescence in site hybridization
• Using probes on interphase cells to look for abnormalities in chromosome numbers

Question 17

What recessive conditions often present without a Fx?

Answer 17

• Haemoglobinopathies (1 in 20 – ethnicity)
• Ashkenazi jewish panel (7 conditions, 1 in 25 to 1 in 100)
• CF (1 in 25 – Northern Europe)
• Spinal muscular atrophy (1 in 40)
• Fragile X syndrome (1 in 200)

Question 18

What is Robertsonian translocation?

Answer 18

Rearrangement on Acrosomic Chromosomes

Question 19

What re acrocentric chsomosomes?

Answer 19

Chromosomes with a small P arm

Examples (13, 14, 15, 21, 22)

Question 20

Balanced vs unbalanced translocation in Trisomy 21

Answer 20

• Most common is 14;21
• If they are balanced, has not loss any genetic material it will not cause any problems for the individual but may cause problems for offspring when inherited
• Balanced translocation = carrier status and that will have no implication to individual unless genetic information has been lost
  But it can occur in the offspring
• Unbalanced translocation between chromosome 14 and 21 leads to trisomy 21 = Down Syndrome

Question 21

How does unbalanced translocation cause Down Syndrome?

Answer 21

Question 22

Microarrays (DNA chips)

Answer 22

• DNA sequences and/or gene expression
• Can look at SNPs
• Can look at larger changes – number of chromosomes and copy number variations

Question 23

What are chromosomal microarrays?

Answer 23

• Array CGH (comparative genome hybridization) and SNP arrays
  o Also called molecular karyotyping
• Probes (25 base oligonucleotides along entire genome)
• Variable resolution
• For deletions and microdeletions

Question 24

When should prenatal molecular karyotyping be performed?

Answer 24

• a fetal abmormality identified on ultrasound scan
• Nuchal translucency is >3.5mm
• A banded (classical cytogenic) karyotype identifies a complex change
• A family member has a microdeleton syndrome and a pregnancy is at risk

Question 25

What dooes the result of molecular karyotyping show?

Answer 25

- Normal result does not exclude genomic abnormality - Presence of small deletion/duplication does not mean pathogenic - Some region of homozygosity may suggest autosomal recessive condition and/or consanguinity - Incidental findings

Question 26

What is pre-implantation genetic diagnosis?

Answer 26

- Require IVF - One or two cell from 3 day old dividing zygote Can do DNA testing, FISH, now chromosomal microarrays

Question 27

What are the analytes in the second trimester maternal serum screening test? and what indicates an increased risk of Trisomy 21

Answer 27

* a-fetoprotein (Reduced) * Oestriol (Reduced) * hCG (Increased) * Inhibin A (Increased)

Question 28

What are the analytes taken in the first trimester?

Answer 28

* hCG * PAPP-A If both are reduced = Increased Risk of Tri18 If hCG is increased and PAPP-A is reduced = Increased risk for Trisomy 21