Lecture 13: A Clinical Perspective on Genetics

What are the four key metrics for evaluating a medical screening test?

• Sensitivity: true positive rate (detects disease when present).

• Specificity: true negative rate (rules out disease when absent).

• PPV: probability of truly having disease given a positive result.

• NPV: probability of truly not having disease given a negative result.

How does disease prevalence affect PPV?

• Low prevalence = most positive results are false positives, even with a good test.

• High prevalence = positive results are much more likely to be true positives.

• Same test can perform very differently across different populations.

How does maternal age affect the PPV of cfDNA testing?

• PPV is much lower in young women due to low baseline prevalence of aneuploidy.

• The same high sensitivity/specificity produces very different PPVs at age 20 vs. age 40.

What structural abnormalities are NOT detected by genetic testing alone?

• Congenital heart defects, neural tube defects, facial clefts, skeletal dysplasias.

• Ultrasound remains essential for detecting these structural anomalies.

• Genetic tests and ultrasound are complementary, not interchangeable.

What is nuchal translucency (NT), and what does an elevated measurement suggest?

• Fluid collection at the back of the fetal neck, measured by ultrasound at 11–14 weeks.

• Elevated NT associated with trisomies 21/18/13, Turner syndrome, triploidy, and structural anomalies (cardiac, diaphragmatic, skeletal).

• The larger the NT, the lower the chance of a normal birth outcome.

What is fetal cell-free DNA (cfDNA), and what are its key biological properties?

• Placental DNA circulating in maternal blood (not actually fetal cells).

• Only a small fraction of total cfDNA is fetal, especially early in pregnancy.

• Detectable from ~5 weeks; cleared rapidly after delivery.

• Detects large chromosomal abnormalities.

  • Vanishing twin/twin demise can cause false positives.

What is the Robertsonian translocation form of Down syndrome, and why does it matter clinically?

• Chromosome 21 fuses with another acrocentric chromosome (most commonly 14), creating a balanced carrier parent.

• Unlike standard trisomy 21, this form is inherited; family members should be tested.

• A balanced carrier parent has significantly elevated recurrence risk compared to standard trisomy 21.

What are the two main DNA technologies used in prenatal genetics?

• Genotyping/CGH (chip technology): detects known mutations and copy number variants, no cell culture needed.

• Whole-exome sequencing: can detect abnormalities in fetuses with multiple anomalies; limited by cost and turnaround time.

What are the advantages and disadvantages of chromosomal microarray (aCGH)?

• Advantages: fast, automated, detailed, no cell culture needed, can use autopsy specimens.

• Disadvantages: expensive, ~3.4% variants of uncertain significance, cannot detect balanced translocations or mosaicism.

• Parental samples often needed; pre- and post-test counseling required.

What are the three invasive diagnostic techniques for prenatal genetics?

• Preimplantation Genetic Diagnosis (PGD): before implantation; errors possible, confirmation usually recommended.

• CVS: 10-13 weeks, samples placental tissue; slightly higher procedure loss rate.

• Amniocentesis: 15-20 weeks, samples amniotic fluid; lower loss rate than CVS.

What is the difference between karyotype and FISH as diagnostic tools?

• Karyotype: identifies all aneuploidies and large rearrangements, 99% accurate, takes 7-14 days.

• FISH: faster (2–3 days), panels available for common trisomies, but not considered fully diagnostic on its own.

  • Fluorescent probe test that binds to specific chromosome regions to quickly detect common aneuploidies.

• Both can be performed on CVS or amniocentesis samples.

Why should genetic testing be offered to all pregnant patients, not just older women?

• 85% of all births occur in women under 35.

• The majority of Down syndrome births occur in younger women simply due to higher birth rates in that group.

• All patients should be counseled about available screening options regardless of age.

What is the carrier status screening panel, and what is a key takeaway?

• Large panels (420+ genes, 36,000+ clinical variants) can screen for carrier status of many recessive conditions.

• Everyone carries 2–3 pathogenic variants.

  • This is normal.

• Clinically relevant only when both partners carry a mutation in the same gene.

What are the pitfalls of genetic screening?

• Non-paternity may be inadvertently revealed.

  • Non-paternity = the assumed father is not the biological father of a child.

• Adult-onset disease findings create ethical complexity.

• Consanguinity increases the risk of recessive conditions.

  • Consanguinity = two people who are biologically related by blood having a child together.

• cfDNA is now sensitive enough to replace karyotyping in recurrent pregnancy loss or fetal demise of abnormal-appearing fetuses.

What is the newborn heel stick screening?

• Mandated by law; varies by state (Indiana screens for 43 conditions + hearing loss).

• Blood drawn from newborn heel, tests for metabolic, endocrine, and hematologic disorders.

• Number of conditions screened has grown dramatically since the 1990s.

What is the "But if it's YOU" concept from the lecture?

• Statistically, a low population risk looks tiny on a grid (one small red square among thousands of blue ones).

• But for the individual patient receiving that result, the emotional experience is 100%; statistics feel irrelevant.

• This is the core challenge of genetic counseling: translating population statistics into personal meaning.

What is the key counseling point when a patient receives a positive cfDNA result?

• cfDNA is a screening test, not diagnostic.

  • Positive results always require confirmation (CVS or amniocentesis).

• Studies show a significant proportion of high-risk cfDNA results are false positives.

• Patients should never be counseled to terminate based on cfDNA alone.