Prenatal exome sequencing versus targeted gene panel for evaluation of fetal congenital heart defects

Abstract

In children and adults, exome sequencing has a higher diagnostic yield than targeted gene panels for both familial and sporadic congenital heart disease. However, these approaches have not been compared in the prenatal setting. Given differences in cost and insurance coverage, we sought to evaluate the yield of exome sequencing versus targeted gene panels for prenatal diagnosis when a congenital heart defect is present. Retrospective cohort of 44 pregnancies with prenatal ultrasound findings of congenital functional or structural heart defects, either isolated or in combination with other fetal anomalies, for which exome sequencing identified a likely pathogenic (LP) or pathogenic (P) variant thought to be causative of the fetal phenotype. All included cases had normal karyotype and/or microarray. Commercial laboratories offering targeted gene panels for prenatal diagnosis of cardiac disorders were identified using an internet search with the terms: “congenital,” and “cardiac defect,” or “cardiomyopathy,” or “heart defect,” or “heart disease.” We then reviewed each panel to determine if the variants would have been detected if the panels were used. The primary outcome was the proportion of P or LP variants identified through exome sequencing that also would have been identified by targeted gene panels. Nine commercial laboratories were identified that offer prenatal diagnosis for congenital heart disease. Three of the nine laboratories offered two applicable panels with different numbers of genes. There was an average of 140 genes per panel, ranging from 6-398. Targeted panels would have detected 7-52% of the 44 variants detected by exome sequencing. Fourteen P or LP variants (14/44, 32%) identified by exome sequencing would not have been detected by any of the targeted gene panels. Only one genetic variant (CHD7) would have been correctly identified by all laboratories. Following a normal karyotype and/or microarray, exome sequencing confers a diagnostic advantage over targeted gene panels for evaluating congenital heart defects identified on prenatal imaging.