Why is NIPT the Vanguard of Genomic Medicine? More than 2M tests performed worldwide since tests became available. Industry has driven innovation. Clinical impact: 70% reduction in invasive procedures (worldwide). Has had consequences on maternal medicine.
Expanding test menus have changed the paradigm for prenatal medicine.
Prenatal is the most mature and translated are of genomic medicine. NIPT functions as well as a crude liquid biopsy.
Why is prenatal most mature? We are measuring cell free placental DNA, mixed with maternal DNA. A liquid placental biopsy. Placental, really.
Tests for Down syndrome , Edwards syndrome, patau syndrome in high risk populations have high sensitivity and specificity. Chance of false neg are 1 in 1054, 1 in 930 and 1 in 4265 respectively. These are just screening tests, but they are VERY good screens.
Contrasts with general population, where probabilities of false negatives are lower, but the prevalence of those issues is lower.
Case for/against routine screening for CNVs:
For: may impact care, independent of maternal age, 1.7% have significant CNVs.
Against: clinical use unproven, high false positive rates, increase in procedures which may be invasive.
Study done showed you needed at least 10 million reads to detect 1Mb copy number variant.
Common micro deletions in testing panels: DiGeorge, Prader-Willi/Angelman, Jacobsen, Langer-Giedion, Cri du chat, Wolf-Hirschhorn, 1p36. All of them are large (3-9.8Mb). Do not align with ultrasound abnormalities.
Example focusing on DeGeorge.
RAT (Rare Autosomal Trisomies)
used a bioinformatics quality control parameter to identify potentially abnormal cases.
MT16: interesting. Anecdotally, in mosaics (since it never exists in non-mosaic) the percent of cells in the child can be a marker for complications.
Decisions should not be made upon NIPT screens. 6% of pregnancies with positive screen results for Trisomies terminated the pregnancy without properly confirming results! [Hope I got that right… might be misunderstood.] Should do amniocentesis, because placental results may not agree, and screens may not actually reflect what’s going on in the fetus.
Tumours are often caught this way. May be a source of false positives.
Bioinformatics errors are possible.
Not much published on pregnancy termination based on the tests.
[Notes are incomplete at the end…]