OC06.05: Adequacy of expanded rasopathies panels for fetuses with isolated increased nuchal translucency: an evaluation of gene coverage

This study aims to evaluate the adequacy of expanded RASopathies Next-Generation Sequencing (NGS) panels in capturing genes associated with isolated increased nuchal translucency (iNT) in fetuses. We conducted a review of two meta-analyses assessing the incremental yield of exome sequencing in fetuses with iNT (Pauta et al. 2022; Mellis et al. 2023). Two additional meta-analyses were excluded - one due to the absence of specific gene listings (Girolamo et al. 2023) and the other for focusing solely on RASopathies genes (Mastromoro et al. 2023). Causative genes for iNT, as identified in the meta-analyses, were cross-referenced with our extended RASopathies panel, comprising 274 genes associated with RASopathies, lymphatic and lysosomal disorders, and congenital anemias. Additionally, the panel included the 28 genes linked to fetal hydrops, as described by Sparks et al. 2020. The meta-analyses revealed 31 cases of iNT with pathogenic or likely pathogenic variants in causative genes. Notably, 12 of these cases (39%) involved genes that were not covered by our expanded RASopathy panel. The excluded genes were TAB2, RERE, ANKRD1, GATA4, NSD1, SETD2, TMEM231, ECE1, NR2F2, and FGD1. Our findings suggest that the application of an expanded RASopathy panel for fetuses with iNT may result in the oversight of 39% of causative genes identified by exome sequencing.