EP06.12: Prospective reanalysis of unsolved prenatal exome sequencing: diagnostic yield and contribution of postnatal/post‐mortem findings

30-40% of fetuses with structural defects remain unsolved after karyotype, chromosomal microarray and exome sequencing. This study presents the results of a reanalysis of unsolved prenatal ES (pES) and investigates the contribution of postnatal/post-mortem phenotyping to identify relevant variants. Prospective reanalysis of pES data was performed in unsolved fetuses enrolled in the AnDDI-Prénatome cohort study. Postnatal/postmortem data up to 3 years were merged with prenatal findings using human phenotype ontology terms. The reanalysis involved updating the bioinformatic processing of the raw data and periodic querying of the raw pES data using a GREP query. The reanalysis was performed in 58/94 unsolved pES (62%), including 8 variants of unknown significance. Clinical examination at birth was available for all live newborns and 12 terminated fetuses with postmortem examination, identifying additional findings in 26/58 fetuses (44%). The contribution of postnatal/post-mortem phenotyping updates to the identification of relevant variants appeared to be limited. Only one new diagnosis was made not because of the additional clinical data provided by the postnatal update of the phenotype, but because of the new implication of the SNAPC4 gene in the human disease. Only one of the three additional VUS identified by reanalysis was also considered thanks to additional features provided by postmortem examination. In conclusion, in the case of unsolved pES, the benefit of prospective reanalysis of unsolved pES appears to be limited, even over time. It may be more appropriate to offer postnatal short-read genome sequencing rather than pES reanalysis with postnatal/postmortem phenotyping update to establish causal diagnosis.