Whole Exome Sequencing (WES) enhances the diagnostic rate of perinatal autopsy: A prospective clinical utility trial with implications for prenatal diagnosis

Abstract

Genomic classification is rapidly becoming a routine and integral part of diagnosis in pathology. Perinatal pathology is following this trend. The aims of this study were to determine the utility of WES in perinatal autopsy for congenital anomalies and to model the outcome of WES as a prenatal test. A total of 131 probands with congenital anomalies who underwent post mortem examination were referred by pathologists to the study. 82 probands were considered suitable for sequencing. The parents of 5 declined enrolment and 10 could not be consented. 67 probands were enrolled. Autopsy identified specific diagnoses in 11 cases (17%). WES identified specific diagnoses (‘pathogenic’ or ‘likely pathogenic’ variants) in 23 cases – a diagnostic rate of 35%. The combined diagnostic rate of autopsy and sequencing was 38%. A geneticist blinded to the autopsy findings reviewed the probands’ antenatal imaging reports and recommended a gene list to model the clinical utility of prenatal WES. The use of antenatal sequencing in this cohort would have identified a specific diagnosis in 18 of the 23 cases with positive sequencing findings. In conclusion, WES doubles the diagnostic rate of autopsy for congenital anomalies and our data supports the prenatal use of genomic sequencing.