P826: Development of a predefined gene list for childhood onset secondary findings via fetal exome sequencing

Results: Vistara was ordered for 57 cases in which ultrasound-detected fetal abnormalities were present or the family history indicated screening.Of the total cohort, 6 (11%) resulted in miscarriage or fetal demise, 1 (2%) had a termination of pregnancy, 2 (4%) had a neonatal demise, and 18 (32%) were lost to care.Six tests identified a pathogenic variant (6/57, 11%); 47 (82%) were negative and 4 (7%) provided 'no result.'Among the positive cases, 2/6 (33%) identified pathogenic variants consistent with tuberous sclerosis complex (TSC), 2/6 (33%) identified pathogenic variants consistent with RASopathies, and 2/6 (33%) identified pathogenic variants associated with osteogenesis imperfecta (OI).Vistara was sent most frequently for the following indications (percent frequency in parentheses, not exclusive): multiple anomaly phenotypes (21%), cystic hygroma (18%), congenital heart disease (11%), increased nuchal translucency (9%), family history of SGD (confirmed molecular etiology) (9%), short long bones <5%ile (5%), advanced paternal age (4%), cardiac rhabdomyoma (4%), family history of SGD without a known molecular etiology (CHARGE and Ehlers-Danlos syndrome, type unknown; 4%).Less frequent indications (2% and less) included: ventriculomegaly, bowed long bones, limb anomalies, increased nuchal fold, pleural effusion, renal anomalies.Diagnostic yield by indication was highest for the following indications: cardiac rhabdomyoma (2/2, 100%), family history of genetic condition with confirmed molecular etiology (which included RASopathy, thanatophoric dysplasia, and OI) (2/5, 40%), cystic hygroma (1/10, 10%), multiple fetal anomalies (1/12, 8%).Of those patients that had a positive Vistara, only 1/6 (16%) had confirmatory diagnostic testing during pregnancy; remaining patients had confirmatory genetic testing on cord blood after birth.This indicates a positive predictive value of 100% in this cohort.Seven (7/57, 12%) received alternative diagnoses through other cell-free DNA based testing, direct DNA testing after invasive procedure, or postnatal genetic testing via cord blood.Conclusion: Diagnostic yield of cfDNA for SGD using the Vistara platform by Natera resulted in an 11% diagnostic yield when fetal ultrasound abnormalities, family history of SGD with or without a known molecular etiology, and/or advanced paternal age are present.A significant proportion of the cohort (12%) had other genetic diagnoses that required alternative testing.Our overall diagnostic yield (11%) is substantially higher than when Vistara is used in an unselected cohort.Future studies are required to determine the best practices for use of cfDNA for SGD including use in unselected vs selected populations, impact on pregnancy outcomes, and patient perspectives on this technology.