Clinical Genetics and Pregnancy Flashcards
(33 cards)
When may a clinical geneticist be required during a pregnancy?
If there is an FH of disease that may affect the pregnancy, either the foetus or mother
If there is an unexpected finding in pregnancy:
• Genetic testing
• USS
If a previous pregnancy / child has malformations
If a test report needs to be clarified or further understood
How to genetically test a baby in utero?
Required foetal DNA:
• From the placenta - Chorionic Villus Biopsy/Sampling (CVS)
• Skin / urine cells - amniocentesis
• Blood - foetal blood sampling
Can also acquire foetal DNA from maternal serum, with non-invasive prenatal testing (NIPT)
When is CVS done?
Usually at ~11.5 weeks; it should be done <12 weeks
Issues assoc. with CVS?
Miscarriage risk of 1-2%
Tissue viability is good
There is a risk of CONFINED PLACENTAL MOSAICISM (discrepancy between the genetic makeup of the baby and placenta)
When is amniocentesis done?
16 weeks +
Issues assoc. with amniocentesis?
Miscarriage risk of 0.5-1%
Tissue viability is poor
When is foetal blood sampling done?
Not commonly used but, when used, it is at 18 weeks +
Issues assoc. with foetal blood sampling?
Miscarriage risk of 1-2%
Tissue viability is good
When is foetal DNA from maternal blood (NIPT) used?
8 weeks +
Issues assoc. with NIPT?
No risk of miscarriage
Tissue viability is stable
However, only limited analyses is currently available and not all chromosomes can be checked
Analyses methods that are available?
For the whole genomes: • Standard karyotype (in metaphase) • Array CGH (aCGH) • Quantification of foetal DNA in maternal serum • Whole genome sequencing
Targeting:
• Point mutation testing
• Fluorescence In-Situ Hybridisation (FISH) - not used unless for demonstration purposes; it is useful when the missing piece of chromosome is too small to see
• Quantitative Fluorescent PCR (QF-PCR) - used to rapidly count the chromosomes, e.g: from amniocentesis
What can aCGH detect?
Chromosomal imbalances (NOT BALANCED TRANSLOCATIONS)
Extra chromosomal material
Missing chromosomal material
Define a mutation?
Genetic change that causes disease
Define a polymorphism?
Genetic variation that is not disease-causing per se
Includes:
• Single Nucleotide Polymorphisms (SNP) - single base changes
• Copy Number Variations (CNV) - insertions or deletions of DNA segments
Differences between mutations and polymorphisms?
Mutations tend to be:
• De-novo, i.e: arising in the child and not present in either parent
• Bigger
• Affect a known gene
• Previously reported in the same phenotype
Polymorphisms tend to: • Normal parent has it • Smallar • Affecting an 'empty' genetic region • Previously reported as a polymorphism
Purpose of QF-PCR?
Rapid counting of specific chromosomes
When is aCGH of chromosome analysis used?
High risk of chromosomal trisomy on screening
Fetal abnormality on scanning:
• Small size, esp. if symmetrical growth failure
• Increased nuchal thickness (NT)
• Structural malformation, e.g: of brain or heart
Parent has balanced chromosomal rearrangement
Methods of prenatal screening in Scotland?
Dating USS, with serum biochemistry (~12 weeks):
• Increased NT may be seen (suggestive of Down’s syndrome)
Serum screening at ~16 weeks:
• Maternal blood test to look for biochemical markers of Down’s syndrome
20 week detailed scan (AKA foetal anomaly scan):
• Look for other fetal abnormalities
What is NIPT currently used for?
Sex determination and trisomy testing
It is also occasionally used to check for chromosome deletions or for single genes
Why is NIPT more difficult that it seems?
Only 10% of the DNA comes from the foetus; the rest is maternal
What should be done in the following situation?
Mrs Pink, who is 10 weeks pregnant, comes to see you. She has a son who is affected with DMD.
Use NIPT for foetal sexing:
• If female, reassure the patient, as females are unaffected by DMD
• If male, do CVS to check whether DMD is present
NOTE - medically, foetal sexing is useful to check for X-linked conditions
What should be done in the following situation?
Mrs Green is 12 weeks pregnant; her serum biochemistry and NT measurement give a risk of 1/40 that the baby is affected with Down’s syndrome.
………
What should be done in the following situation?
Mrs Blue, who is 18 weeks pregnant, comes to see you. A detailed scan has shown that her baby has an AV septal defect, commonly seen in Down’s syndrome.
Do amniocentesis, as she is 15 weeks +, and use aCGH
NIPT is not the best option here, as that looks for specific chromosomes, not all of them; an AV septal defect can be caused by numerous genetic disorders, so all the chromosomes must be checked
NOTE - in this case, the cause was DiGeorge syndrome
Also, aCGH detects small deletions, e.g: 22q11 deletion
Following this, the patient can decide on TOP
Types of chromosomal changes that can cause disease?
Aneuploidy:
• Extra chromosomes
• Fewer chromosomes
Rearrangements inc:
• Translocations
• Inversions
Deletions or duplications
