Diagnostic yield of whole exome data in fetuses aborted for conotruncal malformations

Objective We investigated a custom congenital heart disease (CHD) geneset to assess the diagnostic value of whole-exome sequencing (WES) in karyotype- and copy number variation (CNV)-negative aborted fetuses with conotruncal defects (CTDs), and to explore the impact of postnatal phenotyping on genetic diagnosis. Methods We sequentially analyzed CNV-seq and WES data from 47 CTD fetuses detected by prenatal ultrasonography. Fetuses with either a confirmed aneuploidy or pathogenic CNV were excluded from the WES analyses, which were performed following the American College of Medical Genetics and Genomics recommendations and a custom CHD-geneset. Imaging and autopsy were applied to obtain postnatal phenotypic information about aborted fetuses. Results CNV-seq identified aneuploidy in 7/47 cases while 13/47 fetuses were CNV-positive. Eighty-five rare deleterious variants in 61 genes (from custom geneset) were identified by WES in the remaining 27 fetuses. Of these, five pathogenic or likely pathogenic variants (PV/LPV) were identified in five fetuses, revealing a 10.6% (5/47) incremental diagnostic yield. Furthermore, RERE:c.2461_2472delGGGATGTGGCGA was reclassified as LPV based on postnatal phenotypic data. Conclusion We have developed and defined a CHD gene panel that can be utilized in a subset of fetuses with CTDs. We demonstrate the utility of incorporating both prenatal and postnatal phenotypic information may facilitate WES diagnostics.