A systematic review to assess the utility of genomic autopsy using exome or genome sequencing in cases of congenital anomalies and perinatal death.

PURPOSE: Exome or genome sequencing (ES or GS) can identify genetic causes of otherwise unexplained congenital anomaly and perinatal death (PND) but is not routine practice. The evidence base for 'genomic autopsy' following termination of pregnancy for fetal anomaly (TOPFA) and PND has been synthesised to determine the value of this investigation.

METHODS: We conducted a systematic review and meta-analysis of studies meeting pre-specified inclusion criteria, and containing ≥10 cases of TOPFA or PND (with or without major congenital abnormality), where ES or GS was conducted. We determined test performance, including diagnostic yield, accuracy and reliability. We also reported outcomes associated with clinical utility and harms, where described.

RESULTS: From 2,245 potentially eligible studies, 32 publications were eligible and had data extracted; representing 2,120 cases that could be meta-analysed. No diagnostic accuracy or comparative studies were identified, although some analysis of concordance between different ES/GS methodologies could be performed. Studies reporting parent-related outcomes or long-term follow-up did not do so in a systematic or quantifiable manner.

CONCLUSION: Evidence suggests that approximately 1/4 to 1/3 of fetal losses associated with TOPFA or unexplained PND are associated with a genetic cause identifiable on ES or GS - albeit this estimate varies depending on phenotypic and background risk factors. Despite the large body of evidence on ES and GS, little research has attempted to validate the accuracy of testing, nor measure the clinical or societal outcomes in families that follow the diagnostic investigation in this context.