EP18.17: Whole exome sequencing in prenatal diagnosis: anomaly of low diagnostic yield and incidental findings management

Prenatal genetic diagnosis has enhanced pregnancy management and counselling. Whole exome sequencing (WES) can identify pathogenic variants in additional cases with normal karyotype and negative chromosomal microarray analysis (CMA) but has several limitations such as incidental findings. This study aims to determine the incremental yield of WES and its limitations. This is a prospective cohort study in a referral centre. The parents of fetuses who had structural abnormalities with normal karyotype and negative CMA and who underwent a WES were included. By use of WES of the fetuses and parents (parent-fetus trios), we determined the incremental yield of WES for pathogenic/likely pathogenic variants and the rate of incidental findings. During the study period, 154 cases were included. 33% of provided WES was for multiple organ anomalies. Among the isolated anomalies, WES was performed for increased nuchal translucency (NT) ≥3.5mm (21%), anomalies in the corpus callosum (CC) (19%), fetal cardiac anomalies (7%), musculoskeletal disorders (5%), and other indications. Therefore, WES identified an incremental yield of 19% for pathogenic or likely pathogenic variants. We identified a diagnostic rate of 11% for agenesis of the CC, 5% for hypoplastic CC, and 15% for increased NT (variants referring to RASopathy disorders: PTPN11, LZTR1, KMT2D and NFIB). Additionally, the overall diagnostic rate for isolated hydramnios and isolated hydrothorax was 50%, with a limited number of cases. However, the rate of incidental findings was 21%. Most of them refer to genes responsible for cancer or hematological and cardiac disorders (46%). WES improves genetic diagnosis and counselling of fetal structural anomalies in fetal medicine with a diagnostic rate of 19% with normal karyotype and negative CMA. The high rate of incidental findings required the providers to present developed counselling with parents before suggesting a trio WES.