Genetic Risk

Question 1

Reference to haemophilia X-linked inheritance in the Talmud

Answer 1

Question 2

Indication for prenatal testing

Answer 2

Question 3

Noninvasive prenatal testing methods

(First or Second trimester)

Answer 3

Maternal blood tests: Serum may reflect fetal physiology

Ultrasound: Direct visualization of morphology

cell-free Fetal DNA seq: 5-20% of maternal cfDNA is cffDNA during a pregnancy, increasing slightly over the pregnancy course. High false positive rate for partial aneuploidies, mosaics. Currently only recommended for high risk pregnancies.

Question 4

“Screening test” vs “diagnostic test”

Answer 4

Screening: Has non-zero error, is not definitive. Usually more high-throughput

Diagnostic: Definitive. Has essentially zero error.

Question 5

Invasive prenatal testing

Answer 5

Amniocentesis: Collect amniotic fluid for fetal cells for karyotyping, genotyping, sequencing, array CGH, etc. Risk of misscarriage from 0.1% to 0.3%.

Chorionic villus sampling: Collect sample from the chorionic villus. May be done earlier in pregnancy, but has a higher miscarriage rate (~0.5%) with a chance for limb defects (~1/2000). May also provide false information due to mosaicism between the villus and the fetus.

Question 6

Options for IVF

Answer 6

Preimplantation genetic testing: Offers ability to diagnose before pregnancy but after conception using IVF. At the 8-cell stage, one of the cells can be removed, leaving a 7-cell embryo. By amplifying each of the 2 chromosomes from that cell, genetic testing can be done, and the remaining 7 cells still form a perfectly normal embryo.

Question 7

Phenylketonuria

Answer 7

Results in intellectual disability

Question 8

Guthrie cards

Answer 8

method of storing blood spots from heel sticks in newborns on filter paper.

Used to measure certain metabolites, such as phenylalanine (phenylketonuria), in blood that may be indicative of disease.

Question 9

Conditions frequently screened for in infants or prenatally

Answer 9

Question 10

WHO Screening Criteria

Answer 10

Question 11

Cost-Benefit Analysis of Screening

Answer 11

Question 12

False positive rate

Answer 12

Rarer diseases have a higher ratio of false positives to true positives. As a result, rarer diseases need a higher specificity to maintain the same ratio of false positives to true positives. Note that false positives should really include “less severe” cases who have the disorder, would be detected by screening and confirmed in follow-up testing, but would would not need the preventive treatment because they would not have an adverse outcome. Estimating the number of such cases requires a good understanding of the natural history of the disorder across the clinical spectrum