Prenatal screening and diagnosis Flashcards
(33 cards)
1
Q
Discuss identification of structural abnormalities
-Screening in first trimester (2)
-Screening in second trimester (2)
-Rates of structural abnormalities identified for:
-CNS, GIT, Cardiac, NTD, Abdominal wall defects, Limbs and bones
A
- Screening in the first trimester
-Not done
-Can pick up 50% of major structural abnormalities at NT scan but need further scanning in second trimester to clarify dx and prognosis - Screening in the second trimester
-25% of fetal conditions manifest in the second and third trimesters
-Women with suspected abnormalities should be referred to tertiary centre for confirmation. Detection rate 3 x better - Detection rates for structural abnormalities
-CNS - 75%
-GIT - 50%
-Cardiac - 25%
-Open NTD - 90%
-Abdominal wall defects - 90%
-Limbs - 75%
2
Q
Discuss genetic carrier screening
-Incidence (1)
-Major types of inheritance in healthy parents (2)
-Who should be screened (3)
-Which conditions are frequently tested for and their carrier incidence (5)
A
- Incidence
-1:400 people are affected by inherited conditions - Major types of inherited conditions of healthy parents
-X linked recessive
-Autosomal recessive - Who should be screened
-Offer to couples who have do NOT have a an increased risk of being a carrier based on their personal or family histories
-People with increased carrier risk based on personal or family history should be referred to a clinical geneticist for consideration of diagnostic testing
-In NZ screening only funded for haemoglobinopathies. - Which conditions are frequently tested for
-Cystic fibrosis 1:25 NZ, 1:35 Aust - 1:5000 affected
-Spinal muscular atrophy 1:50 - 1:10 000 affected
-Fragile X 1:332 1:7000 affected
-1:240 couples are at risk of having a child with one of these conditions
-1:1000 couples have an affected child
3
Q
Discuss an approach for genetic carrier screening
-History (2)
-Basic screening (1)
-Additional screening (5)
-Types of additional screening (2)
A
- History
-Family history of genetic conditions and consanguinity from all couples intending to have a child
-Ideally do prior to conception to increase management options - Basic screening
-Offer all women basic thalassemia screening - free in NZ - Additional screening
-Provide information on carrier screening to all women prior to pregnancy or in first trimester
-Genetic screening should only be offered for conditions that majorly impact quality of life
-Advise that this screening is not funded - Types of additional screening
-Limited panel - CF, Spinal muscular atrophy, Fragile X
-Extended panel investigates
>1000 autosomal and X-linked recessive conditions
Should not be offered routinely as find variants of uncertain significance.
Should only be done with stringent pre and post test counselling
4
Q
Discuss genetic carrier screening types
-Sequential screening (2)
-Couple screening (4)
A
- Sequential screening
-Woman is tested first and if carrier then partner is tested
-Lower cost - Couple testing
-One step screening where both ppl are tested at same time
-Faster and less referrals to genetic counselling
-More expensive
-Results invalid if reproductive partners changed
5
Q
Discuss options if carrier status is detected
A
- Conceiving naturally and testing child after birth
- Conceiving naturally and dx test in utero - CVS/Amnio
- IVF with pre-implantation genetic testing
- Use donor sperm or egg or embryo
- Adoption
- Not having children
6
Q
Discuss cystic fibrosis genetic carrier testing
-Gene tested for (1)
-Chance of having a child with CF (1)
-Methods for diagnosis (4)
A
- Gene tested for
-CFTR - cystic fibrosis transmembrane conductance regulator gene - Chance of having a child with Cf if both parents are carriers - 1:4
- Methods for diagnosis
-Pre-implantation
-Amnio/CVS
-Guthrie heel prick at delivery
-Cannot currently do on NIPT
7
Q
Discuss genetic carrier screening for haemoglobinopathies
-Type of inheritance
-Type of disease (2)
-Screening method (2)
-Diagnosis
A
- Inheritance type - autosomal recessive
- Type of disease
-Thalassemias
-Sickle cell - Screening methods
-Haemoglobin electrophoresis
-Cannot do NIPT - Diagnosis
-CVS or amnio
8
Q
Discuss outcomes of genetic carriers of alpha thalassemia
-Mother (–/aa) and father (–/aa) have two alpha gene. Both missing same two.
-Mother (–/aa) has two alpha genes and father (aa/-a) has 3 alpha genes
-Mother (aa/–) and father (-a/-a) are both missing two alpha genes but not the same ones
A
- (–/aa) + (–/aa)
-25% non carrier (aa/aa)
-50% carrier (–/aa)
-25% Barts hydrops (–/–) - (–/aa) + (-a/aa)
-25% non carrier
-25% carrier but 3 alpha genes
-25% carrier but 2 alpha genes
-25% (–/-a) - HbH disease - (aa–) + (-a/-a)
-50% carrier with 3 alpha genes
-50% HbH disease
9
Q
Discuss outcomes for genetic carriers of beta thalassemia
-Carrier with one normal and one abnormal gene for both couples
-Carrier with one normal and one abnormal gene + non-carrier
A
- Both parents carriers of an abnormal gene
-25% chance - non-carrier
-50% carrier
-25% of beta thalassemia major as both genes altered - One parent a carrier and one 2 x normal genes
-50% non-carriers
-50% carrier of beta thal
10
Q
Discuss MSS1/MSS2 screening
-Counselling to women (10 points)
A
- All women should be offered to women in the first trimester
- Should be offered irrespective of clinician’s perception of woman’s likely choice
- Women can opt out of screening - voluntary
- Should include the following in clear simple language
-Description of conditions screened for
-Differences between screening and diagnostic tests
-Pros and cons of different tests
-Possibility that tests can reveal abnormalities other than those expected
-That if the condition is diagnosed then genetic support will be offered
-That management can include TOP and that gestation will impact type of TOP
11
Q
Discuss MSS1/MSS2
-Disorders screened for
-Factors affecting screening results
-Screening types for multiple pregnancy
A
- Disorders screened for
-T13, T18, T21 (make up 66% of aneuploidy). T21 makes up 52% - Factors affecting screening
-BMI
-IVF
-Smoking
-Twin and higher order pregnancies - Screening types for multiple pregnancies
-Twins - MSS1/NIPT. Sens reduced to 72-80%
-Triplets - MSS1
12
Q
Discuss maternal age and aneuploidy
-Used for screening
-Risk of T21 at 20,30, 40, 50yrs
A
- Used as a screening test
-Part of MSS1 and Mss2
-Used alone has sensitivity of 40% - Risk of T21
-20 years - 1:2000
30 years - 1:900
40 yrs - 1:94
50 yrs - 1:4
13
Q
Discuss nuchal translucency
-When to perform (2)
-Utility of screening for chromosomal anomalies (3)
-Conditions it is raised in (6)
-Other testing if NT >3.5 (2)
A
- When to perform
-11-13+6
- If CRL 56-84mm - Utility of screening for chromosomal anomalies
-Part of MSS1 screening
-NT + Maternal age had sensitivity of 75%
-NT >3mm has 10% risk of anomalies, >6mm has a 90% risk - Conditions raised in
-Cardiac dysfunction
-Fetal anemia
-Skeletal dysplasia
-Chromosomal anomalies - Other testing if NT >3.5mm
-Ref to MFM
-Early anatomy - can do on same scan
14
Q
Discuss MSS1 testing
-What it involves
-When to do it
-Cut off for increased chance
-Sensitivity and specificity and PPV for T21
-Significance of PAPP-A
A
- What MSS1 involves
-Maternal age + NT + PAPP-A + BHCG
-Can add in additional findings to increase sens - nasal bone, ductus venosus flow, tricuspid valve flow (contraversial) - When to do
-NT 11-13+6 or if CRL >55mm
-Bloods 9-13+6 - Cut off for increased risk - 1:250
- Sensitivity and specificity
-85% sensitive and 95% specific. PPV = 7-10% - Significance of PAPP-A
-Produced by the syncitiotrophoblasts
-Low is abnormal
-<0.3MoM has RR of 2.6 for IUGR
15
Q
Discuss MSS2
-What it involves
-When to perform
-Cut off for high chance
-Sensitivity and specificity and PPV for T21
A
- What it involves
-Maternal age + AFP, Inhibin-A, Estriol, HCG - When to perform
-14-20 weeks - Cut off for high chance
-1:250 - Sensitivity and specificity for T21
-Sensitivity 75%
-Specificity - 93%
-PPV 2-3%
16
Q
What are the soft markers for aneuploidy (5)
A
- Absent nasal bone
- Echogenic intracadiac focus
- Echogenic bowel
- Ductus venosus wave form
- Tricuspid valve flow
17
Q
Discuss NIPT
-What the test measures for (1)
-What is fetal fraction (2)
-What influences fetal fraction (5)
-How much fetal fraction is needed for a test (1)
-How is it analysed (1)
A
- What does it measure
NIPT measures cell free DNA in the maternal plasma from the syncitiotrophoblasts - What is the fetal fraction
Fetal fraction is the amount of placental DNA that makes up all cell free DNA.
At 10 weeks this is about 10% - Factors influencing fetal fraction
-Gestation - fetal fraction increases with advancing gestation
-Maternal BMI (decreased with increasing BMI)
-Low PAPP-A (small placenta and reduced fetal fraction)
-Aneuploidy
-Twins (Less per fetus cfDNA in didi twins) - Fetal fraction required for reporting - 2-4%
- How is it analysed
-Computerised DNA sequencing to look at preselected chromosomes or whole genome
18
Q
Discuss NIPT
-What does it test for (5)
-How can in be used in clinical practice (3)
-What should it not be used for (5)
A
- What does it test for
-Trisomy 13, 18, 21
-Fetal sex
-Sex chromosome aneuploidy - but less accurate
-Single gene disorders
-Will be able to look at RhD status - How can it be used
-First and second trimester screening test
-Second tier screening in those who received increased MSS1/2 testing.
-Woman wishing for another level of screening - When should it not be used
-As the basis of TOP
-If a definitive dx is required
-If there is a structural abnormality
-If the MSS1 risk is higher than 1:10
-Not as a substitute for NT scan for twins (need morphology and chorionicity scan)
19
Q
Discuss NIPT
-Sensitivity
-Specificity
-NPV for low risk result
-PVV for high risk result
-Sensitivity for sex aneuploidy (2)
A
- Sensitivity - 99%
- Specificity - 99%
- NPV for low risk result - 99.99%
- PPV for high risk result - 81%
- Sensitivity for sex aneuploidy
-89% for XO
-95% for others.
20
Q
Discuss NIPT
-What are the advantage (6)
-What are the disadvantages (6)
A
- Advantages
-High detection rate
-Very low false positive rate <1:10,000
-Larger gestational window for screening with earlier detection
-Does not require highly skilled personnel
-Can detect sex chromosome abnormalities
-Potential to expand diagnostic potential - Disadvantages
-Not diagnostic
-Not as accurate for sex chromosome abnormalities - confounded by placental and somatic mosaicism
-1-6% un reportable
-No NT scan so don’t get early anatomy information
-Doesn’t screen for all abnormalities
-Cost
21
Q
Discuss NIPT
-Amount of tests where a result is not obtained
-What should be done if no NIPT result can be obtained
-Causes of ‘no call’ result
A
- Amount of no call results - 1-6%
- Management if no call result obtained
-Offer repeat NIPT (50% have result)
-Offer detailed anatomy or diagnostic testing
-Offer MSS - Causes of no call result
-Low fetal fraction at early gestational age
-Sub-optimal sample collection
-Fetal karyotype can result in reduced fetal fraction (T18)
-Maternal obesity
-Multiple pregnancy
22
Q
Discuss indications for CVS and amniocentesis (6)
A
-Increased risk of screening - MSS1/2 or NIPT
-Previous chromosomal abnormality
-Parents are affected by genetic condition or are found to be carriers of a recessive trait
-Age >35yrs
-Structural abnormality on USS
-Early onset IUGR
23
Q
Discuss chorionic villous sampling
-Timing (1)
-Methods (1)
-Advantages (1)
-Disadvantages (5)
-Miscarriage rate (2)
A
- Timing
-10 - 13+6 - Methods:
-USS guided needle aspiration bx of the placenta. Usually TA but can be TV
-Screen for blood borne viruses prior to procedure - Advantages
-Allows for earlier diagnosis and therefore earlier TOP if desired - Disadvantages
-Subject to placental mosaicism -1-2%
-More technically demanding
-Risk of limb reduction defect if done before 11/40
-Chance of maternal contamination - 1%
-Subject to placental location - posterior might not be possible. - Miscarriage rate
-1-2% but old data - likely <0.5%
-0.22% at specialist centres
-1% if twin pregnancy
24
Q
Discuss amniocentesis
-Timing (1)
-Method (1)
-Advantages (3)
-Disadvantages (2)
-Miscarriage rates (2)
A
- Timing
>15 weeks when chorion and amnio have fused - Method
-Sample of amniotic fluid - 20-30mL is drawn under sterile technique with USS guidance
-Screen for blood borne viruses prior to procedure - Advantages
-Lower miscarriage rate
-Not restricted by location of placenta
-Doesn’t pick up mosaicism - Disadvantages
-Late diagnosis
-Increased risk talipes - Miscarriage rate
-1-2% old data Likely <0.5%
-0.11% in specialist centres
-1% if twin pregnancy
-Operator dependant
25
Discuss CVS and amniocentesis
-Maternal risks (6)
-Fetal risks (5)
1. Maternal risks
-Miscarriage
-Chorioamnionitis
-Haemorrhage
-Haematoma
-Rh sensitisation
-Uterine contractions
2. Fetal risks
-Fetal infection. <1:1000 but higher if blood born infection
-Fetal injury
-Rupture of membranes
-If CVS performed <11 weeks increased risk limb reduction defects
-If amniocentesis performed before 14 weeks - increased fetal loss and talipes
26
Discuss diagnostic tests used in CVS and Amniocentesis: Conventional karyotype
-What it measures (2)
-How long it takes to process (1)
1. What it measures
-Stains chromosomes from cultured fetal cells for microscopic inspection
-Looks at chromosomal number, length, banding pattern to 5-10 mega bases
2. Processing time
-2 weeks
27
Discuss diagnostic tests used in CVS and amniocentesis:
Fluorescent in situ hybridisation
-What it looks for (3)
-Benefits (1)
-Limitations (3)
1. What it looks for
-Rapid aneuploidy testing
-Can also look for specific microdeletions
-Used in conjunction with karyotype
2. Benefits
-Quick preliminary diagnosis - 48hrs
3. Limitations
-Need to interpret false positive results with caution and use in conjunction with karyotype and USS findings
-False negs: only exclude full trisomies so doesn't rule out structural chromosomal abnormalities
-Results can be inconclusive if mosaicism present
28
Discuss diagnostic tests for CVS and amniocentesis: Chromosomal microarray analysis
-What it looks at (5)
-What it doesn't look at (1)
-Limitations (1)
1. What it looks at
-High resolution analysis of whole genome
-Looks for copy number variants
-Identifies large (5-10Mbp) and submicroscopic (<5Mbp) DNA variations
-First tier test for fetal structural abnormalities - detects more pathogenic aneuploidies than other methods
-Can look for single nucleotide polymorphisms
2. What it doesn't look for
-Can't pick up balanced translocations
3. Limitations
-Detection of variants of uncertain significance 5%
29
Discuss pre-implantation genetic testing
-Indications (4)
-Indication for pre-implantation screening (2)
-Indication for preimplantation diagnosis (1)
-Advantages (1)
-Disadvantages (2)
1. Indications
-Increased chance of genetic condition based on personal and family history
-Genetic carrier status
-Multiple miscarriages
-Lack of success with multiple embryo transfer
2. Indication for pre-implantation screening
-Recurrent miscarriages
-Lack of successful embryo transfer
3. Indication for preimplantation diagnosis
-Perform in those seeking an embryo transferred which is not affected
4. Advantages
-Reduces risk of genetic abnormality and can request TOP
5. Disadvantages
-Higher risk of NIPT failure for NIPT and MSS1 with IVF
-Subject to mosaicism error
30
Discuss RANZCOG recommendations for prenatal tests for chromosomal abnormalities (17)
1. Should be explained and offered to all women in first trimester
2. Should be voluntary
3. If the test shows increased risk of chromosomal abnormality then genetic counseling should be available
4. Acceptable first trimester screens = NIPT or MSS1
5. Couples opting for NIPT should be informed about revealing gender, sex anueploidy and possible unknown maternal conditions
6. Acceptable second trimester screens = NIPT or MSS2
7. The use of NIPT as a second tier screening test for women with increased MSS should be discussed as well as the pro and cons of this vs dx testing vs doing nothing.
8. Dx testing with amnio or CVS should be undertaken before definitive management decisions
9. Routine screening for genome wide chromosomal abnormalities and microdeletions is not recommended
10. For multiple pregnancy first trimester USS should be done regardless of chromosomal screening choices
11. NIPT is OK in multiple pregnancy but has increased failure chances
12. In triplets and higher screening for chromosomal conditions should be performed with first trimester USS markers
13. If direct access to dx testing is preferred this should be allowed with appropriate counseling
14. Preconception screening is preferrable to antenatal screening for heritable genetic conditions
15. A careful Hx of couples prior to conception of heritable traits should be taken and those with RF should be referred to genetic counseling.
16. Carrier screening info for the more common conditions should be available to all women (CF, Fragile X, MSA, Haemaglobinopathies)
17. All pregnant women should be offered thalassemia carrier status screening. Specific assays should be considered for high risk ethnic groups
31
Discuss early pregnancy screening for PET
-Types of screening
-Sensitivity and false positive rates
-What is is predicting
-RANZCOG recommendation
1. Types of screening
Clinical risk factors
-Past or FHx of PET, Underlying medical disorder, Multiple pregnancy
-Assessment of HTN, BMI
Combined clinical, USS (Uterine artery doppler) and biomarkers (PAPP-A and PLGF)
2. Sensitivity and false positive
-May be as high as 95% and 5% respectively. Some issues with the studies
3. What it is predicting
-Looks at early onset PET <34 weeks. Not predictive of late onset PET (Much more common)
4. RANZCOG recommendation
-Routine clinical screening for all pregnant women for PET is recommended
-Use of composite screening tools is yet unclear
32
Discuss fragile X syndrome
-Number who are carriers
-Genetic basis
-Phenotype (5)
-Epidemiology
1. Number who are carriers
1:332 (1: 250-800)
2. Genetic basis
-Trinucleotide repeat disorder (CGG) in FMRI gene. >200 repeats in full mutation
-X linked dominant with reduced penetrance
3. Phenotype
-Mild to severe intellectual disability
-Most common monogenetic cause of autism
-Long face with prominent jaw and forehead
-Hyperflexible fingers
-Large ears
4. Epidemiology
1:7000 males 1:11 000 females
33
Discuss Spinal muscular atrophy
-Carrier numbers
-Genetic cause
-Pathophysiology / phenotype
-Screening considerations
1. Carrier numbers
1:50
1:6000 affected
2. Genetic cause
-Mutations to the SMN1 gene resulting in reduced expression of SMN protein important for nerve conduction to striated muscle
-Some SMA not linked to mutations of this gene
3. Phenotype
-4 types of SMA defined by timing of onset
-Progressive with weakness and atrophy of spinal and proximal muscles as they do not recognise nerve stimulation
-No impact on intelligence
-Symptoms depend on severity
-Most severe have breathing difficult and can die in infancy
5. Screening considerations
-Cannot pick up all SMA as may be other causes
-Cannot tell the severity of SMA by screening
