Genetics: Prenatal Diagnosis Flashcards
8 indications for referral to prenatal diagnosis
- 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
Karyotope of normal female
46,XX
Karyotype of normal male
46,XY
Trisomy 21 Karyotype (Down Syndrome)
47,XX+21
5 characteristics of Trisomy 21 (Down sydrome)
- Hypotonia
- Characteristic dysmorphic features
- Congenital heart defects (40-50%)
- Hirschprung, duodenal atresia, others
- Intellectual disability
Trisomy 18 Karyotype
47,XY,+18
5 characteristics of Trisomy 18
- 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
Karyotype of Trisomy 13
47,XY,+13
7 characteristics of Trisomy 13
- 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
Klinefelter Syndrome Karyotype
47,XXY
Karyotype of Turner Syndrome
45,X
5 characteristics of Klinefelter syndrome
- Poor beard growth
- Breast development
- Under-developed testes
- Tall stature
- Infertility
7 characteristics of Turner Syndrome
- Characteristics facial features
- Web of skin
- Constriction of aorta
- Poor breast development
- Under-developed ovaries
- Short stature
- Infertility
One risk factor for trisomies
Advanced maternal age (NOTE: Turner syndrome is NOT associated with this)
Explain the frequency of chromosome abnormalities linked to maternal age throughout gestation
Decreased frequency due to demise (miscarriage)
Threshold age where it is appropriate to offer amniocentesis (benefit outweighs risk of procedure)
35
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
- Down Syndrome (trisomy 21)
- Trisomy 18
- Spina bifida
3 parameters that are important in a screening program
- Sensitivity (detection rate)
- Positive predictive value
- False positive rate
Goal of a screening program
Maximize sensitivity and minimize FP
Define sensitivity of a genetic screening test
% affected fetuses that have positive result
Define positive predictive value of a genetic screening test
% screen positive cases that are truly affected
Define false positive rate of genetic screening test
% screen positive cases that are unaffected
Sensitivity of advanced maternal age screening program
~30% of affected pregnancies detected
NOTE: Reason = most women have their pregnancies under 35 so less total over 35
3 fetoplacental products used in 2nd trimester maternal serum screening
- 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
Fetal condition associated with increased AFP
Open neural tube defects (i.e. spina bifida)
NOTE: Nowadays detectable by US very well instead of msAFP
3 aspects of the 1st trimester screening program
- Muchal translucency thickness (NT) by ultrasound
- Serum markers
- Pregnancy-associated plasma protein A (PAPP-A)
- B-hCG
Define nuchal translucency
Normal to have fluid under skin, but abnormal to have a large amount under the skin, around the neck
4 Risks associated with finding increase nuchal translucency
- Associated with congenital heart defects and other abnormalities
- 20-30% have adverse pregnancy outcome
- Fetal demise
- Preterm delivery
- Low birth weight
1st and 2nd trimester integrated screening programs
- 1st tri = NT, PAPP-A (hold results)
- 2nd tri = various combinations of AFP, uE3, hCG, inhibin-A
New non-invasive prenatal testing program (2010’s)
Circulating cell-free fetal DNA (starting from 10 weeks gestation)
2 points of screening
- Identify younger women who are at increased risk, offer invasive test
- Identify older women who are at decreased risk, avoid invasive test
2 current guidelines for prenatal screening
- Must do screening first, no matter what age
- Only offer prenatal diagnosis if results are positive
4 major malformations that may be found on ultrasound
- Cardiac malformations
- Cystic hygroma (usually Turner Syndrome)
- Omphalocele
- Neural tube defects
6 markers (“soft signs”) for aneuploidy
- Nuchal fold
- Echogenic bowel
- Short femur
- Intracardiac echogenic focus
- “Absent” nasal bone
- 5th finger cilnodactyly
3 reasons why risk of recurrence for is slightly increased by ~1% to have a second child with a chromosome abnormailty
- Parental mosaicism
- Parental predisposition to nondisjunction
- Chance
2 risks of unbalanced offspring
- Miscarriage
- Abnormal liveborn (i.e. malformations, growth and/or developmental delay)
Define teratogen
Agent that can disturb the development of an embryo or fetus.
5 examples of teratogens
- Radiation
- Maternal infections
- Maternal disease (poorly controlled diabetes, phenylketouria)
- Chemicals
- Drugs
2 prenatal diagnosis techniques (to acquire sample)
- Chorionic villus sampling (CVS)
- Amniocentesis
When can CVS be done?
11 weeks
2 technical issues of CVS
- Mosaicism
- Maternal cell contamination in ~4% of cases
When can amniocentesis be done?
14 - 17 weeks or later
2 genetic tests to use on samples for prenatal diagnosis
- Cytogenic studies
- DNA analysis
Information provided by cytogenic studies
Karyotype
Information provided by DNA analysis of prenatal diagnosis sample
- Direct mutation detection, sequencing, etc. for single gene disorders
- aCGH
