(631) Clinical utility of antenatal cfDNA screening for autosomal dominant disorders in the general population

Objective: We sought to evaluate the clinical utility and PPV of commercially available single gene cell free dna (sgNIPT) screening for autosomal dominant conditions in the general OB population.

Study Design: MFM performs primary genetic screening/US in our USA regional perinatal ctr. From 2021-2023, we offered sgNIPT Natera Vistara to all singleton preg. Fetal/newborn DNA was assessed pre/postnatally after abnl US or abnl sgNIPT. Preg were classified as high or low risk for the mother or fetus to have a pathogenic dna variant in 30 prespecified genes. Small sample size precluded exact estimation of sgNIPT accuracy, statistical estimation yielded wide confidence intervals

Results: 4571 preg pts desired sgNIPT after prenatal counseling at median gest age 18 weeks (range 12-36). 12 preg pts had abnl sgNIPT (screen pos rate of 2.6/1000). 6 fetuses were high risk and 6 preg mothers were carriers (4 mosaic and 2 nonmosaic). No high risk pts had relevant personal/family history. 65/4571 assays were uninformative (1.4%). US, newborn physical exam and DNA data was available for all high risk preg whereas only US/newborn physical exam data was available for low risk preg precluding calculation of analytical sensitivity. PPV was 6/6 (100%) for an affected fetus (apert, thanatophoric, sotos, noonan, tuberous, OI). sgNIPT dxed 6/7 clinically affected fetuses (1 cornelia fetus had uninformative sgNIPT). 5/7 affected fetuses had abnl US. Two maternal full mutation carriers had normal fetal US with confirmed abnl fetal dna (OI). Four maternal "low mosaic" carriers (noonan tuberous cornelia) had normal fetal US/DNA; maternal leukocyte dna mutation analysis was normal suggesting presence of somatic tissue mosaicism

Conclusion: sgNIPT screening in the general OB population allows for fetal risk assessment of dominant conditions but "false positive" results can occur due to the presence of maternal dna variants with variable expressivity, incomplete penetrance and somatic tissue mosaicism. Clinicians and families need to be aware of these issues. Ongoing research is needed to assess the sens/spec of sgNIPT for dominant disorders