Prenatal Testing in the Genomic Era Flashcards
AMA cutoff reasoning
- 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
low AFP
-increased risk for DS
abnormal serum screen
warrants offering of amniocentesis
factors influencing changes to ACOG guidelines
- importance of patient autonomy
- improvements in sensitivity of first and second trimester screening
- reduced risk of miscarriage by use of ultrasound in diagnostic procedures
MPSS
- all cfDNA extracted from maternal serum sample is sequenced
- precise molecular counting allows for determination of fetal aneuploidy
targeted sequencing
focused on certain aneuploidies by only studying specific sequences
SNP NIPS
- analysis of SNPs to determine genotype and relative copy number for each chromosome of interest
- differentiates between maternal and placental DNA
ACOG 545
-released May 2012
-recommended NIPS for:
+women 35+
+suggestive u/s findings
+prior pregnancy with Trisomy
+parental translocation
+positive MSS
PPV
percent of positive results that are truly positive
-affected most by test sensitivity
sex chromosome aneuploidy PPVs
between 20-40%
NPV
percent of negative test results that are truly negative
high maternal BMI
leads to low fetal fraction and increases the risk for no-call result on NIPS
no-call results on cfDNA screens
-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
reasons for false positive results
- CPM
- vanishing twins
- maternal malignancy
- unknown factors
ACOG/SMFM 640
-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
ACMG 2016 position statement
-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
ACOG practice bulletin 153
-different screens and tests with RBLs
+importance of informed consent and patient decision-making
prenatal CMA
- 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
CVS loss rate per ACOG 162
1 in 455
amnio loss rate per ACOG 162
1 in 900
ACMG and UCS
- 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
CF carrier screening
- 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
SMA carrier screening
- 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
hemoglobinopathy carrier screening
- 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
low MCV
below 80
ethnicities with know hemoglobinopathy risk
African, Middle Eastern, West Indian, Southeast Asian & Mediterranean
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
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
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
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
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
five elements of informed consent
- competency
- amount and accuracy of information
- understanding
- voluntariness
- authorization
competency in informed consent
can a decision be made based on an understanding of the consequences of the decision
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
sensitivity
ability to detect true positives
specificity
ability to identify those who do not have the disease correctly