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BACKGROUND: Genetic screening has advanced from prenatal cell-free DNA (cfDNA) screening for aneuploidies (cfDNA-ANP) to single-gene disorders (cfDNA-SGD). Clinical validation studies have been promising in pregnancies with anomalies but are limited in the general population.METHODS: Chart review and laboratory data identified pregnancies with cfDNA-SGD screening for 25 autosomal dominant conditions at our academic center. Screening was identified as routine by International Classification of Diseases (ICD) 10 codes and chart review. Ultrasound anomalies or known family history of a condition on the panel were excluded. Retrospective chart review investigated test concordance, outcomes, and phenotypes.RESULTS: cfDNA-SGD was completed for 3480/37 050 (9.4%) pregnancies, of which 2745 (78.9%) were for routine screening. Fourteen (0.51%, 14/2745) had high-risk results defined as pathogenic/likely pathogenic (P/LP) variants: 6 (0.22%) likely fetal variants, and 8 (0.29%) maternal variants with 50% risk for fetal inheritance. Diagnostic testing detected 6/6 fetal and 6/8 maternal cfDNA-SGD variants (2/8 pregnant individuals declined testing but had clinical features on physical exam). Variants were detected in 11/14 pregnancies/newborns and in 9/14 (64.3%) parents/gamete donors. There were no false positives identified by cfDNA-SGD; however, 2 variants were discrepantly classified between the cfDNA-SGD and diagnostic testing laboratories. All pregnancies had normal imaging and 9 had mild postnatal phenotypes. Three terminated pregnancy following diagnostic testing.CONCLUSIONS: Our study demonstrated that 0.51% of routine cfDNA-SGD was high risk, prompting comprehensive evaluation for pregnancies and parents. Routine cfDNA-SGD allowed for early identification and intervention, but raises counseling challenges due to variable expressivity, limited genotype-phenotype correlations, and discrepant variant classification.