Week 2: Aneuploidy screening Flashcards
Why is it important to determine disease mechanism?
Recurrence risk!!
Risk for aneuploidy is related to maternal age T/F?
What is considered AMA for singleton? For twins?
-True!
-AMA for singleton: 35yr
(Historically this is when chance of genetic condition was greater than risk of miscarriage with an amnio)
-AMA for twins: 32yr
General overview about Down syndrome including 3 mechanisms for disease
-Incidence: 1/700 births but higher incidence in pregnancy
-Three mechanisms for DS:
a. Full T21 ~95% of cases
(nondisjunction)
b. Translocations ~3% of
cases
c. Mosaicism ~1% of
cases
-variable ID, DD
-~50% have physical heart defects
-Flat face, flat nose, almond eyes that slant up, Brushfield’s spots, short neck, small ears, short height, single palmar crease
-average life expectancy 60yr
-Natural loss rate: natural rate of miscarrying higher for babies with DS
General overview of Edwards syndrome, T18, including US soft markers and other features
-Incidence: ~1/6000 live births. Overall prevalence ~1/2500
-Most diagnosed prenatally due to higher rate of detectable birth defects
-50% of babies live longer than a week, 5-10% survive beyond one year
-Those that survive have severe ID/DD and cannot live independently
-Heart defects: VSD, ASD, coarctation of the aorta
-Choroid plexus cyst
-omphalocele
-clubfoot/rocker feet
-IUGR, microcephaly, micrognathia
-severe ID and DD
-umbilical or inguinal hernia
General overview about Patau syndrome, T13, including physical features
-Incidence: 1/10,000-1/15,000 live births
-Most diagnosed prenatally
-Median survival 7-10 days, most die within 1 yr
-Cleft lip/palate, heart defects
-polydactyly
-small eyes, absent eyes, hypotelorism
-holoprosencephaly
-NTDs
General overview about Klinefelter syndrome including features
-Incidence: 1/1500-1,000 males, may be underdiagnosed
-Tall stature
-Puberty delay
-Low testosterone, small testes, low sperm count, enlarged breast tissue (increased risk of breast ca)
-Sparse body hair, broad hips
-infertility
-Speech delays, learning disabilities, autism
General overview about Turner syndrome including features
-Incidence: 1/2,000-1/2500 live births, most die before birth
-Short stature, webbed neck, wide spaced nipples and broad chest, low posterior hairline, edema or hands and feet
-Coarctation of the aorta
-Horseshoe kidney, absence or hypoplasia of kidney
-Streak ovaries, amenorrhea
NOT related to AMA
T/F Turner syndrome is related to maternal age
False
What is triploidy and what are the two mechanisms?
-Occurs 2-3% of conceptions
- ~20% of chromosomally abnormal first trimester miscarriages
-Lethal condition
-Dygynic: extra haploid set from egg
-Diandric: extra haploid set from sperm
What are the features of a digynic triploidy?
Dygynic: extra haploid set from egg
+Asymmetric IUGR
+Relative
macrocephaly
+Small, noncystic
placenta
+Can be live born
What are the features of a diandric triploidy?
Diandric: extra haploid set from sperm
+Fetal growth
relatively normal
+Head normal or
microcephalic
+Placenta is large with
hydropic villi
+Usually don’t survive
to term
Risk for aneuploidy is related to maternal age T/F?
What is considered AMA for singleton? For twins?
-True!
-AMA for singleton: 35yr
(Historically this is when chance of genetic condition was greater than risk of miscarriage with an amnio)
-AMA for twins: 32yr
How often do chromosomal abnormalities occur in live births?
What factors increase the likelihood of chromosomal abnormalities?
- ~1/150 live births, prevalence is greater earlier in gestation
-Unlike aneuploidy, del/dups are independent of age with 0.4% risk
Factors:
-AMA
-Parental translocation
-Previous pregnancy with chromosome abnormality
-US findings
-Positive screen test
What about advanced paternal age related to risk for aneuploidy?
-No clearly accepted definition of advanced paternal age, some say 40+yrs
-APA associated with increased risk of new gene mutations
-Most strongly associated with single base substitutions in FGFR2, FGFR3, and RET genes (Pfeiffer syndrome, Crouzon syndrome, Apert syndrome, achondroplasia, thanatophoric dysplasia, MEN2A, MEN2B)
What does ACOG say about screening and diagnostic testing options?
“Prenatal genetic screening and diagnostic testing options should be discussed and offered to ALL pregnant patients regardless of age or risk for chromosome abnormality”
What does prenatal aneuploidy screening tell you?
-Does NOT diagnose a pregnancy with a condition, identifies those at increased risk
-Result is positive (high risk) or negative (low risk)
-These results are either correct or incorrect
-Noninvasive and safe
Sensitivity vs specificity
-Sensitivity: proportion of affected individuals who have a positive result, aka detection rate, 100% sensitivity= correctly identifies everyone who has the condition
-Specificity: proportion of unaffected individuals who have a negative result, aka true negative, 100% specificity= correctly rules out everyone who does not have the condition
What is positive predictive value?
Probability that those with a positive result have the condition
(affected by incidence)
What is negative predictive value?
Probability that those with a negative result do not have the condition
Why is it important for an ultrasound to occur before screening is performed?
-Change in gestational age (may change available screening)
-Miscarriage
-Demise cotwin
-US findings (pt may change to diagnostic testing instead)
What are the three types of aneuploidy screening tests and what do each of them enatil?
- First trimester US with nuchal translucency: measurement in first trimester ultrasound of CRL and NT
- Maternal serum screening: hormone based bloodwork
- cfDNA: DNA based bloodwork, also called NIPT or NIPS
What is nuchal translucency?
-Normal fluid filled subcutaneous space on back of fetal neck
-Measurement taken when CRL between 38-84mm
-Normal is 3mm or less
-Some clinics use above 99th percentile
-Enlarged NT associated with fetal aneuploidy, genetic syndromes, or other structural malformations
-Risk is proportionate to NT measurement
What aneuploidy is more likely when NT is only slightly increased?
What aneuploidy is more likely when NT is greatly increased?
-Slightly increased: T21
-Greatly increased: Turner syndrome
Increased NT is associated with what?
- Aneuploidy
- CNVs - one of most common being 22q11.2 deletion
- Structural abnormalities- cardiac defects
- Multiple genetic syndromes: RASopathies (Noonan), skeletal dysplasias, Cornelia de Lange, SLO
What is a cystic hygroma and other info about it?
-Fluid filled cavity in nuchal region which can extend the length of the fetus
- ~1% of pregnancies
-Frequently develops into hydrops
-Can be seen in 1st or 2nd trimester
+1st trimester: T21
+2nd trimester: Turner
-Poor prognosis even if other abnormalities aren’t present
What hormones are measured in the first trimester AND in the second trimester for maternal serum screening?
First trimester:
-PAPP-A
-hCG
-AFP
Second trimester:
-AFP
-hCG
-uE3
-DIA or inhibin
What unit of measurement are maternal hormones reported in? What is the ideal value for maternal hormones?
-Serum markers reported as: multiple of the median (MoM)
-MoM is a ratio between the patient’s result and the median result appropriate for patient
-Want MoM close to value of 1!
-MoM value of 2 means marker is twice as high as median level for unaffected pregnancy
-MoM of .5 means marker is half as high as median level for unaffected pregnancy
What other factors can influence maternal serum/ hormone screening?
-Gestational age - CRL
-Maternal weight
-Ethnicity
-Singleton vs twin
-Maternal age (donor)
-Past pregnancy hx
-Past pregnancy with aneuploidy
-Maternal diabetes at conception
-Smoker
When does a first trimester screen occur and what does it measure?
- 11w-13w6d
-Measures PAPP-A, hCG (some labs measure AFP)
-Need NT measurement
-Calculates risk for T21 and T18
does NOT screen for ONTDs
When is a sequential screen performed and what does each screen measure?
First trimester draw:
-11w0d-13w6d
-NT measurment
-PAPP-A, hCG
-Sample analyzed and risk for T21 and T18 reported
Second trimester draw:
- 15w0d-24w6d
-AFP, hCG, uE3, DIA
-Risk for T21 and T18
-Includes AFP (ONTDs)
When is a quad screen performed and what does it screen for?
-Only one blood draw needed in the 2nd trimester
-Range vary on labs:
14w0d-24w6d or
15w0d-20w6d
-Measures AFP, hCG, uE3, DIA
-Screens for T21, T18, ONTDs
When is maternal serum alpha fetoprotein (MS-AFP) screen drawn and what does it screen for?
-Can be drawn in second trimester, ranges vary (ideal between 16-18wks)
-Assess risk for ONTDs if not already screened for in first trimester
What pattern of maternal serum markers are consistent with Down syndrome?
High hCG, high DIA/inhibin
“H and I are high!”
What pattern of maternal serum markers are consistent with T18?
Low AFP, low hCG, low uE3
What pattern of maternal serum markers are consistent with ONTDs?
High AFP
What pattern of maternal serum markers are consistent with having twins?
Everything is high - close to 2 MoMs
What pattern of maternal serum markers are consistent with SLO or X-linked ichthyosis?
Very low uE3
When can cfDNA be performed and what does it use for analysis?
-9 or 10 wks - birth
-Analysis of cell-free fetal DNA circulating in maternal blood
-DNA highly fragmented from apoptosis of placental cells
-Most sensitive and specific screening test!!!!!!
What is fetal fraction and what happens to this percentage throughout pregnancy?
-Percent of DNA circulating in maternal blood that is fetal component from the placenta (~3-20%)
-Percentage increases throughout pregnancy!
Explain cfDNA counting method
-Involves the extraction, amplification, sequencing, and subsequent counting of large numbers of DNA fragments in the plasma while allocating them to their chromosome of origin
-Aneuploidy is when there is a relative excessive (trisomy) or deficit (monosomy) in any particular chromosome of interest compared to the expected number
-Cant detect triploidy because relative amount is the same!
-Does NOT distinguish between maternal and fetal DNA
Explain cfDNA SNP method/difference from counting method
-SNPs normal genetic variation used to distinguish between any two individuals
-Deduces fetal genotype
-Can detect triploidy
What conditions are analyzed using cfDNA?
-Core trisomies: T21, T18, T13
-Sec chromo conditions: Turner, Triple X syndrome, Klinefelter, Jacobs syndrome
-Select microdeletion syndromes (vary by lab)
-Triploidy (technology dependent)
-Genome-wide screening for CNVs >7Mb
What are the three possible results one can receive from screening?
-Positive: high risk for pregnancy to be affected
-Negative: low risk for pregnancy to be affected
-No call/non-reportable: lab is unable to determine risk for pregnancy
If a positive cfDNA screening result is called out and a patient asks what the chance is that the pregnancy is affected, what is the patient really asking about?
They are asking about PPV!
This may be reported by the laboratory or need to use a PPV calculator
What are some nuances/issues associated with cfDNA?
-Can determine fetal sex: possibility of fetal sex selection, X-linked conditions
-Does NOT screen for ONTDs
-Test failures: most due to low fetal fraction, redraw vs pursue diagnostic
-False positive/negatives: vanished twin, fetal placental mosaicism
-Maternal cancer
-Maternal chromosome conditions
-Maternal transplant or recent transfusion
AV canal defect should flag for what syndrome?
Down syndrome
If mother or father is carrier for translocation, is probability higher for recurrence at time of amnio?
Mother
