OC20.07: Fetal exome sequencing: yield and limitations observed in a single tertiary centre

To explore the indications and diagnostic outcomes of fetal exome sequencing analyses performed in a single referral centre. 77 unrelated fetal samples underwent exome sequencing between 2012 and 2017. Indications, turnaround time, diagnostic rates, and pregnancy outcomes were analysed. The pregnant women were assessed at average gestational age of 23.6 ± 2.9 (range 14-36) weeks. Average time from sample submission to initial result decreased with time, and in 2017 averaged 25.8 ± 7.2 days. The most common indication for fetal exome sequencing was multiple malformations (21/77, 27%), followed by isolated brain malformations (15/77, 19%). Twelve fetuses (15%) were referred for isolated increased nuchal translucency (IINT). Exome analysis was diagnostic for 16 fetuses. A comparison of cases of fetal malformations vs. IINT showed that exome analysis did not reveal any known or probable pathogenic variants in IINT cases, whereas among fetuses with anatomic malformation, a molecular diagnosis was reached in 16/65 (25%). Proband-only cases received a diagnosis more often than trio exomes. Exome sequencing has the potential to provide molecular diagnoses in cases where conventional prenatal cytogenetic testing is negative. A referral bias of consanguineous cases could account for the high diagnostic rate for proband-only sequencing. Syndrome-specific prognostic information enables parents to make informed decisions, whereas challenges include time limitations and variant interpretation in the setting of non-specific fetal findings. As we report only established disease-gene associations, further segregation and functional studies in a research setting are expected to significantly increase the diagnostic yield.