Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (1150 page)

   NT measurement requires experienced ultrasonographers.

NONINVASIVE PRENATAL TESTING (NIPT)
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   Definition

   The goal of noninvasive prenatal testing (NIPT) is to obtain information on genetic conditions (e.g., Down syndrome) of a pregnancy by analyzing cell-free fetal DNA circulating in maternal blood and maternal DNA using a blood sample drawn from the mother. The ACMG Policy Statement on “Noninvasive Prenatal Screening for Fetal Aneuploidy” emphasizes that “Positive results should be followed-up with an invasive diagnostic test before any decision is made regarding pregnancy termination.” NIPT should not be used as a diagnostic testing but as a screening test.

   Counting method: sequenced DNA fragments are categorized by chromosome and recalculated for the proportion of each chromosome in the total genome; the proportion of DNA from a chromosome of interest is compared to the expected proportion (i.e., chromosome 21 should represent 1.5% of the total genome). Any deviation from the expected proportion is an indication of a possible aneuploidy. This method is looking for the excess of the chromosome in question (i.e., chromosome 21). Trisomy 21 would increase the amount of DNA from chromosome 21 from the expected 1.5–2.25%. One drawback of this method is that since maternal DNA is the majority of the sample, there is a very small change when the fetal and maternal DNAs are analyzed combined and not differentiated.

   Panorama method: differentiates fetal from maternal chromosomes. DNA is extracted from (1) maternal DNA from white blood cells and (2) cell-free DNA (
cf-DNA
) containing maternal and fetal cf-DNA from plasma. Panorama method tests for characteristic markers (
SNP
s) on both maternal chromosomes and on cell-free DNA (cf-DNA) containing both maternal and fetal DNA. Knowing which chromosomes originate from the mother, the Panorama method subtracts the maternal (and paternal if available) chromosome genotypes from the cell-free DNA (cf-DNA) genotypic information, thereby leaving only fetal chromosome genotypes. Additional analyses consider crossovers, frequency data, and possible fetal chromosome copy number to calculate the ploidy of the fetal sample.

   Use

   Fetal screening testing—positive results should be followed up with an invasive diagnostic test before any decision is made regarding pregnancy termination

   Pretest information should be provided by a prenatal care provider, a trained designee or a genetic counselor to ensure that patients make informed decisions.

   Limitations

   Risk assessment is limited to specific fetal aneuploidies (trisomy 13, 18, and 21) at this time. Some platforms also screen for sex chromosome abnormalities. Other cytogenetic or genetic abnormalities (single gene mutations) or disorders will not be detected when trisomy 21, 18, and 13 are the only aneuploidies being screened.

   Chromosomal abnormalities such as unbalanced translocations, deletions, and duplications will not be detected by NIPS.