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Prenatal genetics > Week 2: Aneuploidy screening > Flashcards

Week 2: Aneuploidy screening Flashcards

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1
Q

Why is it important to determine disease mechanism?

A

Recurrence risk!!

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2
Q

Risk for aneuploidy is related to maternal age T/F?

What is considered AMA for singleton? For twins?

A

-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

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3
Q

General overview about Down syndrome including 3 mechanisms for disease

A

-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

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4
Q

General overview of Edwards syndrome, T18, including US soft markers and other features

A

-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

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5
Q

General overview about Patau syndrome, T13, including physical features

A

-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

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6
Q

General overview about Klinefelter syndrome including features

A

-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

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7
Q

General overview about Turner syndrome including features

A

-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

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8
Q

T/F Turner syndrome is related to maternal age

A

False

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9
Q

What is triploidy and what are the two mechanisms?

A

-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

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10
Q

What are the features of a digynic triploidy?

A

Dygynic: extra haploid set from egg
+Asymmetric IUGR
+Relative
macrocephaly
+Small, noncystic
placenta
+Can be live born

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11
Q

What are the features of a diandric triploidy?

A

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

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12
Q

Risk for aneuploidy is related to maternal age T/F?

What is considered AMA for singleton? For twins?

A

-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

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13
Q

How often do chromosomal abnormalities occur in live births?

What factors increase the likelihood of chromosomal abnormalities?

A
  • ~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

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14
Q

What about advanced paternal age related to risk for aneuploidy?

A

-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)

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15
Q

What does ACOG say about screening and diagnostic testing options?

A

“Prenatal genetic screening and diagnostic testing options should be discussed and offered to ALL pregnant patients regardless of age or risk for chromosome abnormality”

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16
Q

What does prenatal aneuploidy screening tell you?

A

-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

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17
Q

Sensitivity vs specificity

A

-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

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18
Q

What is positive predictive value?

A

Probability that those with a positive result have the condition

(affected by incidence)

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19
Q

What is negative predictive value?

A

Probability that those with a negative result do not have the condition

20
Q

Why is it important for an ultrasound to occur before screening is performed?

A

-Change in gestational age (may change available screening)
-Miscarriage
-Demise cotwin
-US findings (pt may change to diagnostic testing instead)

21
Q

What are the three types of aneuploidy screening tests and what do each of them enatil?

A
  1. First trimester US with nuchal translucency: measurement in first trimester ultrasound of CRL and NT
  2. Maternal serum screening: hormone based bloodwork
  3. cfDNA: DNA based bloodwork, also called NIPT or NIPS
22
Q

What is nuchal translucency?

A

-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

23
Q

What aneuploidy is more likely when NT is only slightly increased?

What aneuploidy is more likely when NT is greatly increased?

A

-Slightly increased: T21
-Greatly increased: Turner syndrome

24
Q

Increased NT is associated with what?

A
  1. Aneuploidy
  2. CNVs - one of most common being 22q11.2 deletion
  3. Structural abnormalities- cardiac defects
  4. Multiple genetic syndromes: RASopathies (Noonan), skeletal dysplasias, Cornelia de Lange, SLO
25
Q

What is a cystic hygroma and other info about it?

A

-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

26
Q

What hormones are measured in the first trimester AND in the second trimester for maternal serum screening?

A

First trimester:
-PAPP-A
-hCG
-AFP

Second trimester:
-AFP
-hCG
-uE3
-DIA or inhibin

27
Q

What unit of measurement are maternal hormones reported in? What is the ideal value for maternal hormones?

A

-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

28
Q

What other factors can influence maternal serum/ hormone screening?

A

-Gestational age - CRL
-Maternal weight
-Ethnicity
-Singleton vs twin
-Maternal age (donor)
-Past pregnancy hx
-Past pregnancy with aneuploidy
-Maternal diabetes at conception
-Smoker

29
Q

When does a first trimester screen occur and what does it measure?

A
  • 11w-13w6d
    -Measures PAPP-A, hCG (some labs measure AFP)
    -Need NT measurement
    -Calculates risk for T21 and T18

does NOT screen for ONTDs

30
Q

When is a sequential screen performed and what does each screen measure?

A

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)

31
Q

When is a quad screen performed and what does it screen for?

A

-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

32
Q

When is maternal serum alpha fetoprotein (MS-AFP) screen drawn and what does it screen for?

A

-Can be drawn in second trimester, ranges vary (ideal between 16-18wks)
-Assess risk for ONTDs if not already screened for in first trimester

33
Q

What pattern of maternal serum markers are consistent with Down syndrome?

A

High hCG, high DIA/inhibin

“H and I are high!”

34
Q

What pattern of maternal serum markers are consistent with T18?

A

Low AFP, low hCG, low uE3

35
Q

What pattern of maternal serum markers are consistent with ONTDs?

A

High AFP

36
Q

What pattern of maternal serum markers are consistent with having twins?

A

Everything is high - close to 2 MoMs

37
Q

What pattern of maternal serum markers are consistent with SLO or X-linked ichthyosis?

A

Very low uE3

38
Q

When can cfDNA be performed and what does it use for analysis?

A

-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!!!!!!

39
Q

What is fetal fraction and what happens to this percentage throughout pregnancy?

A

-Percent of DNA circulating in maternal blood that is fetal component from the placenta (~3-20%)
-Percentage increases throughout pregnancy!

40
Q

Explain cfDNA counting method

A

-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

41
Q

Explain cfDNA SNP method/difference from counting method

A

-SNPs normal genetic variation used to distinguish between any two individuals
-Deduces fetal genotype
-Can detect triploidy

42
Q

What conditions are analyzed using cfDNA?

A

-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

43
Q

What are the three possible results one can receive from screening?

A

-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

44
Q

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?

A

They are asking about PPV!

This may be reported by the laboratory or need to use a PPV calculator

45
Q

What are some nuances/issues associated with cfDNA?

A

-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

46
Q

AV canal defect should flag for what syndrome?

A

Down syndrome

47
Q

If mother or father is carrier for translocation, is probability higher for recurrence at time of amnio?

A

Mother

Prenatal genetics (9 decks)

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