Prenatal Testing in the Genomic Era Flashcards
(90 cards)
1
Q
AMA cutoff reasoning
A
- equal risk of miscarriage and risk for affected pregnancy
- cost of testing in any woman over 35y thought to be offset by savings of not having affected babies
2
Q
low AFP
A
-increased risk for DS
3
Q
abnormal serum screen
A
warrants offering of amniocentesis
4
Q
factors influencing changes to ACOG guidelines
A
- importance of patient autonomy
- improvements in sensitivity of first and second trimester screening
- reduced risk of miscarriage by use of ultrasound in diagnostic procedures
5
Q
MPSS
A
- all cfDNA extracted from maternal serum sample is sequenced
- precise molecular counting allows for determination of fetal aneuploidy
6
Q
targeted sequencing
A
focused on certain aneuploidies by only studying specific sequences
7
Q
SNP NIPS
A
- analysis of SNPs to determine genotype and relative copy number for each chromosome of interest
- differentiates between maternal and placental DNA
8
Q
ACOG 545
A
-released May 2012
-recommended NIPS for:
+women 35+
+suggestive u/s findings
+prior pregnancy with Trisomy
+parental translocation
+positive MSS
9
Q
PPV
A
percent of positive results that are truly positive
-affected most by test sensitivity
10
Q
sex chromosome aneuploidy PPVs
A
between 20-40%
11
Q
NPV
A
percent of negative test results that are truly negative
12
Q
high maternal BMI
A
leads to low fetal fraction and increases the risk for no-call result on NIPS
13
Q
no-call results on cfDNA screens
A
-can be related to low ff
-increased risk for aneuploidy (~23%)
+offer GC with diagnostic testing
+repeat testing only provides result 50-60% of time
+namely increased risk for triploidy & Tri18 in which placenta is smaller
14
Q
reasons for false positive results
A
- CPM
- vanishing twins
- maternal malignancy
- unknown factors
15
Q
ACOG/SMFM 640
A
-pretest counseling, RBL
-combined serum &/or NT better than cffDNA for first line testing
+simultaneous first tri screening not recommended
+AFP and/or ultrasound screening recommended in conjunction
-microdeletion cfDNA testing should not be performed routinely
-NIPS should not be used in multiple gestations
16
Q
ACMG 2016 position statement
A
-should not be restricted only to high risk women
+however, should not be used routinely
+still recommends use of 2nd tri AFP and 1st tri ultrasounds
17
Q
ACOG practice bulletin 153
A
-different screens and tests with RBLs
+importance of informed consent and patient decision-making
18
Q
prenatal CMA
A
- per ACOG 162 should be offered whenever an anomaly is seen
- should be offered to any woman undergoing invasive testing
- can identify 6% of cases with an anomaly and normal karyo, 1.7% with abnormal screening and normal karyo
- recommended as part of workup for IUFD
19
Q
CVS loss rate per ACOG 162
A
1 in 455
20
Q
amnio loss rate per ACOG 162
A
1 in 900
21
Q
ACMG and UCS
A
- conditions tested should be serious and patients undergoing it should use it for intent of reproductive decision
- consent to ACMG 56 results (especially adult-onset conditions)
- should only use well-characterized mutations with predictable phenotypes-clinical association
- all labs doing UCS should comply with ACMG best practices
22
Q
CF carrier screening
A
- offered to all reproductive age women
- incidence of 1 in 2500, 1 in 25 carrier frequency in caucasian couples, lower in other populations
- panethnic 23 mutation panel sufficient-CFTR gene sequencing IS NOT
- condition overview: med survival age 42y, primarily affects pulmonary, pancreatic & GI function
23
Q
SMA carrier screening
A
- variability in genotype-phenotype correlation
- incidence of 1 in 6000-1 in 10000, carrier frequency of 1 in 40-1 in 117
- severe condition overview: characterized by degeneration of spinal cord motor neurons leading to skeletal muscle atrophy
24
Q
hemoglobinopathy carrier screening
A
- all patients should have RBC+CBC & a low MCV should prompt further investigation
- hemoglobinelec ethnicity based with known increased risk for Hgb-opathies in certain ethnicities
- normal heme-elec should still be followed-up to rule out alpha-thal
25
low MCV
below 80
26
ethnicities with know hemoglobinopathy risk
African, Middle Eastern, West Indian, Southeast Asian & Mediterranean
27
AJ condition carrier screening
- always: Canavan, Tay-Sachs, CF, familial dysautonomia
| - new: bloom syndrome, familial hyperinsulinism, FA, Gaucher, GSDs, Joubert syndrome, MSUD, MPS-IV, Niemann-Pick, Usher
28
ACOG #690
-gives guidelines for what is an appropriate panel of universal carrier screening
+carrier frequency of 1 in 100 or greater
+well-defined phenotype
+condition would have a detrimental effect on QoL causing ID, DD, handicap, require medical or surgical intervention and have effects early in life
+be able to be diagnosed prenatally and have possible interventions for treatment or delivery that could improve outcomes
+should primarily not include adult-onset conditions
29
elements of pretest counseling for ECS
- outcomes can't always be predicted by conditions screened-phenotypes not always well-defined and detection for rare conditions might not be great
- screen-negative results reduce but do not eliminate residual risk
- panels will change over time, but re-testing is not recommended
30
needs and future directions with ECS
-prospective studies to compare ECS to ethnic-based carrier screening
+patient and provider attitudes
+outcomes-better for children?
-cost-effectiveness studies
-educational tools and decision-making aids for patients
31
CFTR I148T allele
- used to be included in pan ethnic 25 mutation panel and had to be removed b/c it was leading to unnecessary diagnostic procedures
- found more frequently than expected and only disease causing with rarer 3119del6 mutation
32
five elements of informed consent
1. competency
2. amount and accuracy of information
3. understanding
4. voluntariness
5. authorization
33
competency in informed consent
can a decision be made based on an understanding of the consequences of the decision
34
extrapolating women's reactions to prenatal microarray results
- ability to have info felt like an offer that was too good to pass up
- blindsided/unprepared for abnormal results
- uncertainty & unquantifiable risks
- need for support
- toxic knowledge-wanting to close Pandora's box
35
sensitivity
ability to detect true positives
36
specificity
ability to identify those who do not have the disease correctly
37
serum markers
-surrogate markers-not directly related to chromosomal anomaly
+AFP-produced by fetus
+uE3, inhibin, beta-hCG placental
-reported as MoMs to allow more easily explainable results for clinicians, consistency and correction for differences between labs
38
detection rate
- sensitivity
- uses known affected population
- number of correctly identified affected pregnancies
39
false negative rate
- cases of known affected missed by test
| - 100-sensitivity
40
specificity
- population of unaffected
| - how often do we correctly identify unaffected cases
41
false positive rate
- 100-specificity
| - cases of known unaffected incorrectly identified
42
First tri screen
```
-MSS analyses
+hCG
+PAPP-A
+inhibin-not always included
-NT
```
43
second tri screen
*only analytes
-AFP
-uE3
-hCG
+ICT-type of hCG tested by one lab
-inhibin
44
combined/integrated screen
- NT at 10-14w
- 1st & second tri blood draws
- results only given after 2nd set of results
- better detection rate, but slower timeline
45
contingent screen
-NT at 10-14w
-first tri MSS drawn and reported
-second tri MSS only run for intermediate risk
+high risk have diagnostic option
+low risk (~ < 1 in 2000) receive no part two test
46
sequential screen
- NT at 10-14w
- first tri MSS drawn
- second tri MSS drawn
* get part 1 and 2 results
47
uE3 and AFP over time
increase during pregnancy
48
inhibin over time
generally constant throughout pregnancy
49
hCG
decreases during pregnancy
50
DS analytes
```
1st tri
-low PAPP-A
-high hCG
-large NT
2nd tri
-low uE3
-low AFP
-high hCG
-high inhibin
*greater extremes increase risk
```
51
Tri 18 & Tri 13 analytes
```
1st tri
-large NT
-low PAPP-A
-low hCG
2nd tri
-all analytes low
```
52
FASTER trial results
with cut-offs of 1:150 with 1st tri and 1:300 for 2nd tri, sequential had a higher detection rate (94%) than 1st tri at different cutoffs and 2nd tri alone
+higher false positive rate
53
cystic hygroma
protruding sac at the back of baby's neck, indicative of anomaly-sometimes excluded from screening studies because already high risk
54
triple vs quad
added analyte reduces inaccuracy, but increases false positive rate
55
WGS NIPS
- used combination of haplotypes to determine results
- essentially a trio
- we are going to get results we don't yet know how to interpret it
56
NT cut-off
generally larger than 3.0 mm considered high risk
57
large NT associations
- increased risk for Tri 13, 18, 21, Turner
- can indicated other structural anomalies, especially cardiac (10%)
- other single gene conditions (Noonan, multiple pterygium, skeletal dysplasia)
58
non-chromosomal causes of analyte abnormality
-placental insufficiency and abnormalities
+confers increased risk for miscarriage, IUGR, stillbirth, infant death
-identifies higher risk of maternal hypertension, pre-eclampsia and risk of antepartum hemorrhage
-single gene conditions
59
low uE3 levels
associated with SLOS, X-linked (harlequin) ichthyosis
60
high AFP levels
- wrong dates
- multiples pregnancy
- ONTDs, abdominal wall defects
- high risk obstetrical outcomes
- maternal malignancy-VERY HIGH levels
61
ACHE
processes acetylcholine in neurons, should only be in CSF, so presence in amniotic fluid increases risk of ONTD
62
ethnicity-based CS model
limited to a certain group of people because of a high risk for particular genetic conditions
63
population-based CS model
screening for common conditions offered to all individuals
64
pan-ethnic-based CS model
larger than population based-screening because it targets more than common conditions
65
reasons for increased AR condition risk
- founder effect
- societal inbreeding over time or due to geographic isolation and consanguinity
- selective advantage
66
ethnicity melting pot
mixing of ethnicities makes a population-based model of carrier screening challenging
67
genotyping array platforms
- finite number of mutations
- variable detection rate by disease and ethnicity
- should be used in population carrier screening set-up
68
sequencing platforms
-uses NGS technology
-increases the number of variants identified
+do we report all of these if unknown effect?
-theorized higher detection across all populations-still limited in practice
-could use in population screening set-up or when one partner is an identified carrier
69
overall risk to be a carrier of a genetic condition
approximately 1 in 5
70
MPSS limitations
- struggles when regions are GC rich, such as with chr 13
| - cannot distinguish between maternal and fetal cfDNA
71
SNP NIPS limitations
- cannot he used in multiples pregnancies
- due to failure of maternal & fetal DNA to match, can’t be used in pregnancies conceived with egg donors, consanguinity or when mom has had a BMT or organ transplant
72
Limitations of NIPS testing
-studies show at least 16% chromosomal anomalies are missed by this analysis alone (does not include CMA mutations)
-not diagnostic, screening
+mesynchamal core more representative than trophoblastic material measured
-risk for discordant results and no-call result
-low incidence conditions difficult to pickup, PPV low
73
CPM
- can result from abnormal segregation of chromosomes during mitosis or from trisomy rescue
- can cause result discordance, as most of the time abnormality is confined to the placenta
74
T13 and Turner on CVS
- higher risk for CPM
| - consider amnio in place of or in addition
75
Co-twin demise/vanishing twin and NIPS
-in one study 27% all multiples spontaneously reduced in less than 7w
-contribution of this in discordance is unclear
+aneuploid fetuses are more likely to demise
-additional DNA can remain in maternal blood for ____w (at least 2w)
76
Maternal obesity & NIPS
-remodeling of adipose tissue in pregnant women with obesity results in increased release of cfDNA of maternal origin
-circulating concentration of fetal cfDNA doesn’t change, but fraction is reduced
+can be seen in women >170lbs
*testing should not be completed until 14w if maternal BMI is >40
77
High fetal fraction
Could indicate faster placental death
| +often seen in DS
78
Maternal malignancy & NIPS
-Possible outcome that can be identified besides CPM or true aneuploidy
+very abnormal results seen-especially concerning if two chromosomes look funky
-incidence of ~1 in 1000
79
Maternal mosaicism and NIPS
Higher risk of Turner (possibly other sex chromosome aneuploidies too) result on NIPS
+related to mosaicism with increasing maternal age
80
No-call results on NIPS
could be related to:
- failed quality metrics
- low FF
- fetal aneuploidy (2.5x more likely)
81
CVS
-Diagnostic procedure typically done between 11-13w
+increased miscarriage risk before 9w
+culture fails more after 13w
-transcervical v transabdominal depends on location of placenta, fetus number & provider comfort level
82
CVS complications
- risk for SAB May be slightly elevated
- learning curve for providers
- oromandibular limb hypogenesis in fetuses less than 9w
- club foot
- mosaicism
- infection and/or leakage in <0.5% of cases
83
Placenta decidua
- normal
| - placenta attached to uterus until labor when it separated due to contractions
84
Placenta accreta
- abnormal
| - placenta is attached too deeply to uterus
85
Placenta increta
- abnormal
| - placenta is more deeply attached to the muscle wall around the uterus
86
Placenta perceta
- abnormal
| - placenta grows through uterus and can extend to nearby organs
87
Immune hydrops
- Rh negative mother produces anti-D Ab (or k mother with K child, etc)
- risk for fetal and maternal blood to mix high during delivery, amnio, CVS
- can increase the risk for anemia in future pregnancies if Rhogam is not administered
88
MCA Doppler
Measures velocity at which blood is being shunted to fetal brain
-higher number means a sicker baby
89
invasive prenatal testing advances
-used to be standard karyotype and FISH
-now can use CMA
+detects 6% of anomalies with ultrasound finding, but normal karyo
+picks up diagnosis with 13% of MCA cases
-NGS panels
+can help diagnose Noonan, holoprosencephaly, skeletal dysplasia
-WES & WGS on research basis
+NTD & GU defects have had the largest findings at columbia
90
limitations of prenatal WES and WGS
```
-cost
+expensive, insurance often won't cover
-TAT
+findings usually identified late then results can take months sometimes
-secondary findings
+ACMG 56
-who "owns" and receives this information
-future discrimination
```
