OC06.01: Single gene, gene panel and exome sequencing applied in structurally abnormal fetuses with a normal chromosomal microarray analysis

Abstract

Objectives To assess the diagnostic yield of different next generation sequencing (NGS) studies, single gene, gene panel or clinical exome sequencing in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA). Methods During a 4-year period (March 2015-February 2019), NGS studies were performed on fetal DNA extracted from amniocytes or chorionic villi in 57 structurally abnormal fetuses with a normal CMA. NGS studies included a single gene analysis (n = 5), gene panel (n = 26), or clinical exome sequencing (n = 40). Single gene analysis was performed for specific skeletal dysplasias and syndromes caused by a single candidate gene (CHARGE, Mowat-Wilson). A gene panel was applied when there were multiple candidate genes for a specific syndrome or fetal feature (renal anomalies, Noonan syndrome, fetal hydrops, craniosynostosis). Finally, clinical exome sequencing was preferentially used for recurrent or multisystem anomalies with no specific syndrome suspected. In the last year, fetuses with those anomalies were referred to us by 10 collaborating centres. Results In 35% (25/71) of the cases, NGS provided a definitive diagnosis. It was provided in 1/5 (20%) of single gene analyses, in 9/26 (35%) gene panels [4 by CAKUT and 2 by Noonan panels], and in 15/40 (38%) of the clinical exomes [2 Kabuki syndromes in multisystem anomalies, 5 skeletal dysplasias, 4 neurologic anomalies, and 2 suspected arthrogryposes].