Genetics: Prenatal Diagnosis

Question 1

8 indications for referral to prenatal diagnosis

Answer 1

• Advanced maternal age (being phased out)
• Abnormal (positive) results of maternal serum screening
• Abnormal findings on ultrasound
• Previous child with a chromosome abnormality
• Parental chromosome abnormality
• Family history of other genetic disorder or malformation
• Teratogen exposure
• Infertility

Question 2

Karyotope of normal female

Answer 2

46,XX

Question 3

Karyotype of normal male

Answer 3

46,XY

Question 4

Trisomy 21 Karyotype (Down Syndrome)

Answer 4

47,XX+21

Question 5

5 characteristics of Trisomy 21 (Down sydrome)

Answer 5

• Hypotonia
• Characteristic dysmorphic features
• Congenital heart defects (40-50%)
• Hirschprung, duodenal atresia, others
• Intellectual disability

Question 6

Trisomy 18 Karyotype

Answer 6

47,XY,+18

Question 7

5 characteristics of Trisomy 18

Answer 7

• Overlapping fingers
• Rockerbottom feet
• Growth & developmental retardation (severe)
• Congenital heart defect (~90%)
• Most do not live long (central apnea), but rare ones live into early childhood

Question 8

Karyotype of Trisomy 13

Answer 8

47,XY,+13

Question 9

7 characteristics of Trisomy 13

Answer 9

• Holoprosencephaly (60-70%) (failure of brain cleavage –> one lobe)
• Clenched hands and polydactyly (60-70%)
• Cutis aplasia (absence of development of skin)
• Cleft lip and palate (60-70%)
• Cardiac malformations (80%)
• Severe/profound intellectual disability
• Shortened lifespan as in trisomy 18

Question 10

Klinefelter Syndrome Karyotype

Answer 10

47,XXY

Question 11

Karyotype of Turner Syndrome

Answer 11

45,X

Question 12

5 characteristics of Klinefelter syndrome

Answer 12

• Poor beard growth
• Breast development
• Under-developed testes
• Tall stature
• Infertility

Question 13

7 characteristics of Turner Syndrome

Answer 13

• Characteristics facial features
• Web of skin
• Constriction of aorta
• Poor breast development
• Under-developed ovaries
• Short stature
• Infertility

Question 14

One risk factor for trisomies

Answer 14

Advanced maternal age (NOTE: Turner syndrome is NOT associated with this)

Question 15

Explain the frequency of chromosome abnormalities linked to maternal age throughout gestation

Answer 15

Decreased frequency due to demise (miscarriage)

Question 16

Threshold age where it is appropriate to offer amniocentesis (benefit outweighs risk of procedure)

Answer 16

35

Question 17

3 screening programs designed to provide a woman with a more precise risk that that based upon maternal age alone and that she is carrying a fetus with one or more specific genetic conditions

Answer 17

• Down Syndrome (trisomy 21)
• Trisomy 18
• Spina bifida

Question 18

3 parameters that are important in a screening program

Answer 18

• Sensitivity (detection rate)
• Positive predictive value
• False positive rate

Question 19

Goal of a screening program

Answer 19

Maximize sensitivity and minimize FP

Question 20

Define sensitivity of a genetic screening test

Answer 20

% affected fetuses that have positive result

Question 21

Define positive predictive value of a genetic screening test

Answer 21

% screen positive cases that are truly affected

Question 22

Define false positive rate of genetic screening test

Answer 22

% screen positive cases that are unaffected

Question 23

Sensitivity of advanced maternal age screening program

Answer 23

~30% of affected pregnancies detected

NOTE: Reason = most women have their pregnancies under 35 so less total over 35

Question 24

3 fetoplacental products used in 2nd trimester maternal serum screening

Answer 24

• Alphafetoprotein (AFP)
• Unconjugated estriol (uE3)
• Human chorionic gonadotropin (hCG)

NOTE: Median concentration in Down syndrome fetuses sufficiently different to predict increased risk, but does not tell you about the actual health of the fetus

Question 25

Fetal condition associated with increased AFP

Answer 25

Open neural tube defects (i.e. spina bifida) NOTE: Nowadays detectable by US very well instead of msAFP

Question 26

3 aspects of the 1st trimester screening program

Answer 26

* Muchal translucency thickness (NT) by ultrasound * Serum markers * Pregnancy-associated plasma protein A (PAPP-A) * B-hCG

Question 27

Define nuchal translucency

Answer 27

Normal to have fluid under skin, but abnormal to have a large amount under the skin, around the neck

Question 28

4 Risks associated with finding increase nuchal translucency

Answer 28

* Associated with congenital heart defects and other abnormalities * 20-30% have adverse pregnancy outcome * Fetal demise * Preterm delivery * Low birth weight

Question 29

1st and 2nd trimester integrated screening programs

Answer 29

* 1st tri = NT, PAPP-A (hold results) * 2nd tri = various combinations of AFP, uE3, hCG, inhibin-A

Question 30

New non-invasive prenatal testing program (2010's)

Answer 30

Circulating cell-free fetal DNA (starting from 10 weeks gestation)

Question 31

2 points of screening

Answer 31

* Identify younger women who are at increased risk, offer invasive test * Identify older women who are at decreased risk, avoid invasive test

Question 32

2 current guidelines for prenatal screening

Answer 32

* Must do screening first, no matter what age * Only offer prenatal diagnosis if results are positive

Question 33

4 major malformations that may be found on ultrasound

Answer 33

* Cardiac malformations * Cystic hygroma (usually Turner Syndrome) * Omphalocele * Neural tube defects

Question 34

6 markers ("soft signs") for aneuploidy

Answer 34

* Nuchal fold * Echogenic bowel * Short femur * Intracardiac echogenic focus * "Absent" nasal bone * 5th finger cilnodactyly

Question 35

3 reasons why risk of recurrence for is slightly increased by ~1% to have a second child with a chromosome abnormailty

Answer 35

* Parental mosaicism * Parental predisposition to nondisjunction * Chance

Question 36

2 risks of unbalanced offspring

Answer 36

* Miscarriage * Abnormal liveborn (i.e. malformations, growth and/or developmental delay)

Question 37

Define teratogen

Answer 37

Agent that can disturb the development of an embryo or fetus.

Question 38

5 examples of teratogens

Answer 38

* Radiation * Maternal infections * Maternal disease (poorly controlled diabetes, phenylketouria) * Chemicals * Drugs

Question 39

2 prenatal diagnosis techniques (to acquire sample)

Answer 39

* Chorionic villus sampling (CVS) * Amniocentesis

Question 40

When can CVS be done?

Answer 40

11 weeks

Question 41

2 technical issues of CVS

Answer 41

* Mosaicism * Maternal cell contamination in ~4% of cases

Question 42

When can amniocentesis be done?

Answer 42

14 - 17 weeks or later

Question 43

2 genetic tests to use on samples for prenatal diagnosis

Answer 43

* Cytogenic studies * DNA analysis

Question 44

Information provided by cytogenic studies

Answer 44

Karyotype

Question 45

Information provided by DNA analysis of prenatal diagnosis sample

Answer 45

* Direct mutation detection, sequencing, etc. for single gene disorders * aCGH