6. Use of arrays and NGS in prenatal diagnosis

Question 1

What percentage of pregnancies are affected by major congenital abnormalities?

Answer 1

1-1.5%

Question 2

What is the contribution of chr abns to major fetal anomalies?

Answer 2

Account for 20-25%

Question 3

When is prenatal array indicated?

Answer 3

Cases with abnormal ultrasound, where QF-PCR is normal

Question 4

Which findings are reported from a prenatal array?

Answer 4

Only report findings that account for the USS findings or are clinically actionable

Question 5

What are the considerations of array resolution?

Answer 5

Higher resolution may have greater diagnostic utility but also detects more VUSs

Lower density may miss abnormalities

Question 6

What are the advantages of prenatal array over karyotyping?

Answer 6

1. Cell culture not required, therefore faster TAT and exclusion of culture artefacts
2. Greater resolution therefore higher pick up rate

Question 7

What is the pick up rate for prenatal arrays?

Answer 7

2.5% in all referrals, 7% in abn scan referrals

Question 8

What are the disadvantages of prenatal array compared to karyotyping?

Answer 8

1. Requires large quantity of high quality DNA - difficult for prenatal
2. Can’t detect balanced rearrangements
3. Low level mosaicism may be missed (platform dependent)
4. Increased detection of VUSs –> parental anxiety, counselling
5. Risk of incidental findings (BRAC2 deletion, DMD CNVs)

Question 9

If a CNV is found to be inherited from a normal parent, why might it still be pathogenic?

Answer 9

1. AR condition (CNV + SNV)
2. Imprinting effect
3. Incomplete penetrance

Question 10

Why might follow up testing be required?

Answer 10

Karyotyping/FISH for positional info and recurrence risk

Question 11

Why is prenatal NGS important?

Answer 11

Approx 60% of pregnancies with fetal abnormalities on USS don’t have genomic cause identified by QF-PCR, karyotype or array

Question 12

Why is it genomic investigation of fetal abnormalities seen on USS important?

Answer 12

Inform management of the pregnancy, guides prognosis and counselling

Question 13

Which study preceded prenatal WES moving into clinical practice?

Answer 13

Prenatal Assessment of Genomes and Exome (PAGE) study

Question 14

What family structure is used to interpret prenatal WES data and why?

Answer 14

Trio

Enables filtering of variants according to inheritance patterns - therefore speeds up analysis

Question 15

What are the main challenges associated with prenatal WES?

Answer 15

1. VUSs - cause anxiety, make decision making more complex when termination is an option
2. Reporting of incidental findings - not generally reported in fetus but may be in parent
3. Interpretation based on what is visible on USS - limited in comparison to post-natal

Question 16

What genes are tested for prenatally?

Answer 16

Genes which
cause phenotypes which may present in the prenatal period and can be detected on fetal imaging

Question 17

Give an example of an incidental finding that might be reported from prenatal WES?

Answer 17

BRCA1/2 variant in fetus with fanconi anaemia phenotype (congenital hip dysplasia, scoliosis, radial ray anomalies - all non-specific)

Risk of HBOC revealed as part of diagnosis as BRCA1/2 also cause FA