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ABGC > Prenatal Testing in the Genomic Era > Flashcards

Prenatal Testing in the Genomic Era Flashcards

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

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2
Q

low AFP

A

-increased risk for DS

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3
Q

abnormal serum screen

A

warrants offering of amniocentesis

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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
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5
Q

MPSS

A
  • all cfDNA extracted from maternal serum sample is sequenced
  • precise molecular counting allows for determination of fetal aneuploidy
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6
Q

targeted sequencing

A

focused on certain aneuploidies by only studying specific sequences

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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
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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

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9
Q

PPV

A

percent of positive results that are truly positive

-affected most by test sensitivity

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10
Q

sex chromosome aneuploidy PPVs

A

between 20-40%

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11
Q

NPV

A

percent of negative test results that are truly negative

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12
Q

high maternal BMI

A

leads to low fetal fraction and increases the risk for no-call result on NIPS

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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

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14
Q

reasons for false positive results

A
  • CPM
  • vanishing twins
  • maternal malignancy
  • unknown factors
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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

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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

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17
Q

ACOG practice bulletin 153

A

-different screens and tests with RBLs

+importance of informed consent and patient decision-making

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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
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19
Q

CVS loss rate per ACOG 162

A

1 in 455

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20
Q

amnio loss rate per ACOG 162

A

1 in 900

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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
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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
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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
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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
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25
Q

low MCV

A

below 80

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26
Q

ethnicities with know hemoglobinopathy risk

A

African, Middle Eastern, West Indian, Southeast Asian & Mediterranean

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27
Q

AJ condition carrier screening

A
  • always: Canavan, Tay-Sachs, CF, familial dysautonomia

- new: bloom syndrome, familial hyperinsulinism, FA, Gaucher, GSDs, Joubert syndrome, MSUD, MPS-IV, Niemann-Pick, Usher

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28
Q

ACOG #690

A

-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

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29
Q

elements of pretest counseling for ECS

A
  • 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
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30
Q

needs and future directions with ECS

A

-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

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31
Q

CFTR I148T allele

A
  • 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
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32
Q

five elements of informed consent

A
  1. competency
  2. amount and accuracy of information
  3. understanding
  4. voluntariness
  5. authorization
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33
Q

competency in informed consent

A

can a decision be made based on an understanding of the consequences of the decision

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34
Q

extrapolating women’s reactions to prenatal microarray results

A
  • 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
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35
Q

sensitivity

A

ability to detect true positives

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36
Q

specificity

A

ability to identify those who do not have the disease correctly

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37
Q

serum markers

A

-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
Q

detection rate

A
  • sensitivity
  • uses known affected population
  • number of correctly identified affected pregnancies
39
Q

false negative rate

A
  • cases of known affected missed by test

- 100-sensitivity

40
Q

specificity

A
  • population of unaffected

- how often do we correctly identify unaffected cases

41
Q

false positive rate

A
  • 100-specificity

- cases of known unaffected incorrectly identified

42
Q

First tri screen

A 
-MSS analyses
\+hCG
\+PAPP-A
\+inhibin-not always included
-NT
43
Q

second tri screen

A

*only analytes
-AFP
-uE3
-hCG
+ICT-type of hCG tested by one lab
-inhibin

44
Q

combined/integrated screen

A
  • NT at 10-14w
  • 1st & second tri blood draws
  • results only given after 2nd set of results
  • better detection rate, but slower timeline
45
Q

contingent screen

A

-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
Q

sequential screen

A
  • NT at 10-14w
  • first tri MSS drawn
  • second tri MSS drawn
  • get part 1 and 2 results
47
Q

uE3 and AFP over time

A

increase during pregnancy

48
Q

inhibin over time

A

generally constant throughout pregnancy

49
Q

hCG

A

decreases during pregnancy

50
Q

DS analytes

A 
1st tri
-low PAPP-A
-high hCG
-large NT
2nd tri
-low uE3
-low AFP
-high hCG
-high inhibin
*greater extremes increase risk
51
Q

Tri 18 & Tri 13 analytes

A 
1st tri
-large NT
-low PAPP-A
-low hCG
2nd tri
-all analytes low
52
Q

FASTER trial results

A

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
Q

cystic hygroma

A

protruding sac at the back of baby’s neck, indicative of anomaly-sometimes excluded from screening studies because already high risk

54
Q

triple vs quad

A

added analyte reduces inaccuracy, but increases false positive rate

55
Q

WGS NIPS

A
  • 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
Q

NT cut-off

A

generally larger than 3.0 mm considered high risk

57
Q

large NT associations

A
  • 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
Q

non-chromosomal causes of analyte abnormality

A

-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
Q

low uE3 levels

A

associated with SLOS, X-linked (harlequin) ichthyosis

60
Q

high AFP levels

A
  • wrong dates
  • multiples pregnancy
  • ONTDs, abdominal wall defects
  • high risk obstetrical outcomes
  • maternal malignancy-VERY HIGH levels
61
Q

ACHE

A

processes acetylcholine in neurons, should only be in CSF, so presence in amniotic fluid increases risk of ONTD

62
Q

ethnicity-based CS model

A

limited to a certain group of people because of a high risk for particular genetic conditions

63
Q

population-based CS model

A

screening for common conditions offered to all individuals

64
Q

pan-ethnic-based CS model

A

larger than population based-screening because it targets more than common conditions

65
Q

reasons for increased AR condition risk

A
  • founder effect
  • societal inbreeding over time or due to geographic isolation and consanguinity
  • selective advantage
66
Q

ethnicity melting pot

A

mixing of ethnicities makes a population-based model of carrier screening challenging

67
Q

genotyping array platforms

A
  • finite number of mutations
  • variable detection rate by disease and ethnicity
  • should be used in population carrier screening set-up
68
Q

sequencing platforms

A

-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
Q

overall risk to be a carrier of a genetic condition

A

approximately 1 in 5

70
Q

MPSS limitations

A
  • struggles when regions are GC rich, such as with chr 13

- cannot distinguish between maternal and fetal cfDNA

71
Q

SNP NIPS limitations

A
  • 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
Q

Limitations of NIPS testing

A

-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
Q

CPM

A
  • 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
Q

T13 and Turner on CVS

A
  • higher risk for CPM

- consider amnio in place of or in addition

75
Q

Co-twin demise/vanishing twin and NIPS

A

-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
Q

Maternal obesity & NIPS

A

-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
Q

High fetal fraction

A

Could indicate faster placental death

+often seen in DS

78
Q

Maternal malignancy & NIPS

A

-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
Q

Maternal mosaicism and NIPS

A

Higher risk of Turner (possibly other sex chromosome aneuploidies too) result on NIPS
+related to mosaicism with increasing maternal age

80
Q

No-call results on NIPS

A

could be related to:

  • failed quality metrics
  • low FF
  • fetal aneuploidy (2.5x more likely)
81
Q

CVS

A

-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
Q

CVS complications

A
  • 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
Q

Placenta decidua

A
  • normal

- placenta attached to uterus until labor when it separated due to contractions

84
Q

Placenta accreta

A
  • abnormal

- placenta is attached too deeply to uterus

85
Q

Placenta increta

A
  • abnormal

- placenta is more deeply attached to the muscle wall around the uterus

86
Q

Placenta perceta

A
  • abnormal

- placenta grows through uterus and can extend to nearby organs

87
Q

Immune hydrops

A
  • 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
Q

MCA Doppler

A

Measures velocity at which blood is being shunted to fetal brain
-higher number means a sicker baby

89
Q

invasive prenatal testing advances

A

-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
Q

limitations of prenatal WES and WGS

A 
-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

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