Exome sequencing as first‐tier test for fetuses with severe central nervous system structural anomalies

Objectives Prenatally diagnosed central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compare the diagnostic yield of exome sequencing (ES) and chromosomal microarray (CMA) in fetuses with major CNS anomalies. Methods The study included 114 cases following termination of pregnancy (TOP) due to major CNS anomalies. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed by ES to assess its ability to detect CNVs. Results CMA identified a pathogenic or a likely pathogenic (P/LP) copy number variant (CNV) in 11/114 cases (10%). Eighty-six CMA-negative cases were analyzed by ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases, the incidence of P/LP sequence variants was somewhat higher than in non-recurrent ones (12/19=63% vs. 26/67=39%, P=.06). Of the cases resolved by ES, 20/38 (53%) were inherited and carried a significant recurrence risk. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known, non-causative CNVs. Conclusions The high diagnostic yield (>50%) may be the result of this being a highly selected series which included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants, as well as CNVs. This is of particular importance in the time-frame constraints of an ongoing pregnancy, and for correctly assessing the recurrence risk in future pregnancies. This article is protected by copyright. All rights reserved.