The ability of cell free DNA (cfDNA) screening to assess fetal genetic status during pregnancy continues to improve and expand at what feels like an exponential rate. Also known as non-invasive prenatal testing (NIPT), cfDNA screening has been clinically available to screen for common chromosomal aneuploidies in singleton pregnancies since the early 2010’s. This analysis allows for a higher detection rate and positive predictive value for common trisomies in pregnancy rather than traditional maternal serum screening.1 Recently, the American College of Obstetricians and Gynecologists recommended NIPT to all patients, regardless of age or risk; special consideration should still be taken for pregnancies of multiples.
Over time, laboratory testing advances have allowed for the screening of other aneuploidies, microdeletion syndromes, large copy number variants (CNVs), and single gene disorders. Targeted cfDNA analysis for 30 genes known to be associated with spontaneous variants, which contribute to prenatal or childhood onset autosomal dominant diseases, became clinically available in early 2017 thanks to Baylor Genetics’ PreSeekTM screen.
While providing genetic counseling and informed consent for this ever-increasing number of screening options available to patients remains complex, if desired, cfDNA screening can provide valuable information regarding a current pregnancy.
Beyond Aneuploidy Risk Assessment
Traditionally, prenatal screening, such as maternal serum screening, has focused on assessing risk for chromosomal aneuploidy, the risk for which is known to increase with maternal age.2 Advanced paternal age, traditionally considered as 40 or 45 years of age, has relatedly been associated with increased risk for single gene, spontaneous (de novo) variants. These variants can cause genetic disease anomalies in offspring.3 Prenatal screening for variants in the most commonly involved genes allows for risk assessment for those seeking this information due to concern based on paternal age, suspicious ultrasound findings, or family history.
Currently, both biological parental specimens are required for PreSeekTM and serve as controls (comparators) to help interpret the cfDNA data. Accepted parental specimens include blood in a Streck tube from the biological mother or surrogate, and blood in an EDTA tube or saliva from the biological father (and egg donor, if appropriate).
Ultrasounds and Family History
While many of the conditions assessed via PreSeekTM do not exhibit sonographic findings until later in the second or third trimester, some screened conditions, such as Noonan-spectrum disorders and skeletal dysplasias, may exhibit findings earlier in gestation. The pursuit of screening for patients with relevant ultrasound findings helps narrow down the potential gene and variant which could be causing the findings, reduces cost of broader pre- or postnatal diagnostic testing, and streamlines the diagnostic odyssey for patients and families.
The screen can also be utilized in the context of a known paternal family history of a variant in a gene(s) assessed via the screen. While reporting does include risk assessment of all 30 genes on the panel, knowledge of a known familial variant allows for specific scrutiny and reporting of the variant of interest. As maternal cfDNA cannot be distinguished from placental cfDNA, maternal carrier status for a familial variant prohibits fetal assessment for the same via PreSeekTM. However, assessment can still be provided for the remainder of the involved gene and for the additional genes on the screening panel.
As with aneuploidy and microdeletion cfDNA screening results, PreSeekTM‘s gene assessment via cfDNA is a screening tool. Pathogenic and likely pathogenic findings are reported, while variants of unknown significance (VUS) are not included in reporting. Negative results significantly reduce the risk for disease associated with the genes assessed, but do not completely eliminate the risk. Similarly, positive results convey an increased risk for the specific gene and variant identified; however, pre or postnatal diagnostic testing should be performed to confirm the finding. Prenatally, this can include targeted testing via chorionic villus sampling (CVS) or amniocentesis. Postnatally, this is often performed on a blood specimen from the neonate.
Occasionally, analysis will indicate that a parent is also a carrier of the identified variant. If newly identified in the father, confirmatory analysis via Sanger sequencing will be performed and a separate report will be issued indicating his variant status. If identified in the mother, the status of the fetus will be inconclusive due to inability to differentiate from placental DNA and further pre- or postnatal diagnostic testing may be pursued.
Incorporating into Prenatal Care
PreSeekTM‘s cfDNA screening of 30 genes has dramatically impacted prenatal risk assessment and diagnostic testing decision-making. Low-risk results can provide reassurance or direct further testing in alternative directions. Identification of increased risk for the screened conditions allows providers and families to build a plan of care for the duration of the pregnancy, delivery, and neonatal care. This can include genetic counseling regarding results and potential implications, diagnostic testing options, and referrals to additional health care providers.
Want to learn more? Additional information, such as groups of conditions included in the screen, lists of genes assessed and detection rate, ordering information, and a link to the published white paper can be found on the Baylor Genetics website and test menu.
- Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017 Sep;50(3):302-314. doi: 10.1002/uog.17484. Epub 2017 Jul 27. Update in: Ultrasound Obstet Gynecol. 2019 Jun;53(6):734-742. PMID: 28397325.
- Mikwar M, MacFarlane AJ, Marchetti F. Mechanisms of oocyte aneuploidy associated with advanced maternal age. Mutat Res. 2020 Jul-Sep;785:108320. doi: 10.1016/j.mrrev.2020.108320. Epub 2020 Jul 4. PMID: 32800274.
- Cioppi F, Casamonti E, Krausz C. Age-Dependent De Novo Mutations During Spermatogenesis and Their Consequences. Adv Exp Med Biol. 2019;1166:29-46. doi: 10.1007/978-3-030-21664-1_2. PMID: 31301044.