20.05.06 Arrays in PND Flashcards
What percentage of pregnancies are affected with major congenital abnormalities
1-1.5%
What percentage of fetal anomalies are due to chromosomal abnormalities
20-25%
Purpose of arrays in prenatal setting
- To increase resolution and detection of chromosomal abnormalities compared to karyotyping, whilst minimizing detection and reporting of CNVs of uncertain significance
- Ideally report clinically actionable findings, limited to cases with abnormal ultrasound (where rapid aneuploidy is normal)
Advantages of arrays in prenatal setting
- Cell culture not required. Faster TAT and exclusion of culture artefacts
- Higher pick up rate of abnormalities (2.4% increased pick up)
- Known familial balanced translocations, carriers not detected.
Disadvantages of arrays in prenatal setting
- High quality DNA required, not always possible.
- No detection of balanced translocations which could cause a phenotype via gene disruption
- Mosaicism may be missed
- Triploidy could be missed/ misinterpreted
- Culturing may still be required for following, delays TAT
- Follow up costs may be increased (parental studies)
- Detection and interpretation of VUS
- Incidental findings with implications to fetus and parents (BRCA1/2, TP53)
- Some CNVs have variable penetrance
Do higher density arrays increase diagnostic utility
No. Instead leads to increase discovery of benign and VUS.
Recommendations for array testing (working group from European Society of Human Genetics 2011 conference)
- Use same platform for pre/ postnatal settings
- Experience is important in interpretation, knowing strengths and weaknesses of the platform
- High resolution array guarantees a minimum of false negative results
- Interpretation is easier if lab has an in-house dataset, analysed using the same platform.
If a fetus has inherited a CNV from an apparently unaffected parent, pathogenicity cannot be completely excluded due to:
- If deletion is in trans with a point mutation in a recessive condition
- CNV could contain an imprinted gene that has a pathogenic effect when only inherited from one parent
- CNV itself has a pathogenic burden but exhibits incomplete penetrance.
Other considerations for CNV interpretation
- Segregation (in unaffected parent, de novo)
- Genomic region involved (contains OMIM Morbid genes)
- Clinical context.
If a VUS is seen in a fetus, how do you avoid incidental findings when following up parental samples
- Do arrays in parents but restrict to only the location of VUS
- Do FISH (if probes available) or qPCR (depending on size of aberration)
What considerations should be made if mosaicism is identified
- Could be pseudomosaicism or confined placental mosaicisim.
- Need a confirmatory sample, especially if ultrasound findings are expected and not present or are inconsistent with result.
What investigations should be made if a suspected structural imbalance is detected by array
- Conventional karyotyping or metaphase FISH.
- To identify mechanism of aberration and thus gather information on recurrence risk. Likely won’t alter management of pregnancy.
What is the EACH study
- Evaluation of Array Comparative Genome Hybridisation in prenatal diagnosis of fetal anomalies.
- Compared array with karyotyping (after rapid QF-PCR) in fetuses with 1 or more structural abnormality or isolated NT>3.5mm
- Conclusions: robust, acceptable and cost effective diagnostic test that should replace karyotyping in care pathways in fetal testing when one or more structural anomaly or NT>3.5mm is seen on ultrasound after a normal QF PCR result
What local policies may differ with regard to prenatal array testing
- Good communication between lab and clinicians.
- Agreement on what to report to clinician prior to testing, what to report to patient (pathogenic CNV that is not consistent with ultrasound findings), reporting unsolicited findings (findings resulting in increased risk for diseases of known or unpredictable severity for fetus and parents now or in later life).
What is the TAT for prenatal microarrays
14 days
