Genetics E1- Developmental Genetics

When does organogenesis occur (all major organs formed)?

4-8 wks

When are fetal movements felt?

16-18 wks

When is the fetus viable with specialized care?

24-26 wks

What is considered advanced maternal age?

≥ 35 at time of delivery

What is aneuploidy?

Extra or missing chromosome

What is a condition in which there is a discrepancy in the genetic makeup between the cells off the placenta and the cells of the fetus?

Confined placental mosaicism

What is consanguinity?

2 people share a common ancestor

What is residual risk?

Risk that an individual carries an abnormal gene after a negative (normal) screening test result

What is robertsonian translocation?

Structural rearrangement involving 1 or more of the acrocentric chromosomes (13, 14, 15, 21, 22)

What patients would prenatal genetic screening and diagnostic testing be offered to?

*should only have 1 approach, not multiple tests performed simultaneously

All pregnant patients regardless of maternal age or risk of chromosomal abnormality

What is the most sensitive and specific screening test for the common fetal aneuploidies?

Cell-free DNA

When should all patients be offered an ultrasound to screen for fetal structural defects?

Second trimester 18-22 wks

What is the next step for patients with a positive screening test result for fetal aneuploidy?

Genetic counseling & comprehensive US evaluation with an opportunity for diagnostic testing to confirm results

Can prenatal screening methods provide a prenatal diagnosis of aneuploidy?

No

What are the 3 major categories of prenatal genetic screening?

US, maternal serum screening, & NIPS

The risk of fetal aneuploidy ______ with advanced maternal age (≥35).

increases

What were the previous guidelines for invasive diagnostic testing in pregnant women 35 or older?

Offer to women who were at least as likely to have an affected pregnancy as to have a miscarriage from the procedure (risk was thought to be 1 in 200 for both)

*has since confirmed the risk of miscarriage from procedure is lower → offer screening & dx to women of all ages

What is assessed in the first trimester ultrasound?

Anatomy, markers of fetal number to placental position, birth defects and soft markers, measures NT & helps determine due date

What are soft markers?

Subtle changes that alter a woman’s risk for specific types of aneuploidy: echogenic bowel, intracardiac foci, & shortened long bones

What is thickened nuchal translucency (NT) associated with?

Down syndrome, cardiac defects, pending fetal demise, or normal variant

The following features found on prenatal US are characteristic of what condition?

• clenched overlapping fingers

• rocker-bottom foot

Trisomy 18

The following features found on prenatal US are characteristic of what condition?

• cardiac defect (common AV canal)

• cystic hygroma or fetal hydrops

Trisomy 13, 18, & 21

The following features found on prenatal US are characteristic of what condition?

• exomphalos

Trisomy 13 & 18

The following features found on prenatal US are characteristic of what condition?

• duodenal atresia

Turner syndrome (45,X) & Trisomy 21

What does maternal serum screening detect?

Analyzes maternal serum markers (1st tri: B-hCG, PAPP-A; 2nd tri: inhibin A, uE3, AFP, hCG) & risk assessment for common aneuploidies (Trisomy 13, 18, 21), & NTDs

What is a combined first trimester screen with US?

Combines biochemical portion of FTS with NT U/S to provide risk assessment for Trisomy 21 & combined trisomy 18 & 13

What is the quadruple (quad) screening?

Performed bt 15-23 wks, provides risk for Trisomy 21 & 18 and ONTDs by measuring AFP, unconjugated estriol, hCG, and inhibin A levels

What can be drawn if a mother has had first trimester screen (FTS), NIPS, or the diagnostic chorionic villus sampling?

Maternal serum AFP level to provide risk for ONTDS only

*quad should not be ordered if any of these done previously

What is sequential/ integrated screening?

Measurement from 1 blood specimen in 1st trimester and 2nd trimester; provides risk for Trisomy 21, 18, 13, & ONTDs

What is the most efficient serum based screening test with a high detection rate (DR) and low false positive ratio (FPR)?

Sequential / integrated screening

What is noninvasive prenatal screening (NIPS)?

Evaluates fragments of DNA in mother’s blood that comes from the placenta; screens for Trisomy 21, 18, 13, rare sex aneuploidies, & select microdeletions (22q, 15q)

*does NOT eval for ONTDs

What prenatal genetic screening offers higher detection rates and lower false positive rates than maternal serum screens?

NIPS

What is prenatal diagnostic testing?

Techniques in which placental or fetal cells are obtained for genetic testing; false +/- do NOT occur

ex: CVS, amniocentesis

What prenatal diagnostic test involves removing chorionic villi cells from the placenta for genetic testing?

Chorionic villus sampling (CVS)

What risks are associated with CVS?

Miscarriage, confined placental mosaicism (placenta may not function as effectively, growth restriction in 2nd & 3rd trimesters)

What is recommended to test for ONTDs in patients who get CVS?

Maternal serum AFP level

What condition occurs when the tissue of placenta has abnormal number of chromosomes and the tissue of the fetus has normal number of chromosomes?

Confined placental mosaicism

What prenatal diagnostic test involves removing amniocytes through amniotic fluid for genetic testing?

Amniocentesis

Which prenatal diagnostic testing method can test for ONTDs?

Amniocentesis

Which diagnostic procedure is done earlier in pregnancy and has a slightly higher risk for miscarriage?

CVS

What does fluorescence in situ hybridization (FISH) evaluate?

Information on only 5 chromosomes: 13, 18, 21, X, Y

What is the gold standard for diagnosing aneuploidy & provides information on all chromosomes?

Chromosome analysis (karyotype)

What uses comparative genomic hybridization to report on gains or losses throughout the genome, & can detect smaller gains or losses than chromosome analysis?

Microarray

What risks are associated with microarray?

Not being able to detect triploidy & chances that VOUS will be found

What conditions do carrier screening guidelines recommend that all women be screen for?

CF, spinal muscular atrophy, hemoglobinopathies (sickle cell);

What is the downside to pan ethnic & expanded carrier screening?

More people will be found to be carriers for at least one condition when tested

When should a reproductive partner be offered carrier testing?

If a patient is found to be a carrier for an autosomal recessive condition

What should couples with consanguinity be offered?

Genetic counseling to review the increased risks of recessive conditions

What is prenatal genetic screening?

Any testing that is not diagnostic; can have false positives & negatives

What are key family history questions to ask a patient when determining if they should be referred for genetic counseling?

FHx of birth defects, multiple pregnancy losses, intellectual disability, hearing or vision loss at birth, known genetic conditions, & consanguinity in the patient or other parent