Retrospective identification of prenatal fetal anomalies associated with diagnostic neonatal genomic sequencing results

Abstract

Objective: To determine which types of fetal anomalies are associated with postnatal diagnoses of genetic diseases by genomic sequencing and to assess how prenatal genomic sequencing could affect clinical management. Method:This was a secondary analysis of the second Newborn Sequencing in Genomic Medicine and Public Health study that compared fetal imaging results in critically ill infants who had actionable versus negative postnatal genomic sequencing results.Results: Of 213 infants who received genomic sequencing, 80 had available prenatal ultrasounds. Twenty-one (26%) of these were found to have genetic diseases by genomic sequencing. Fourteen (67%) of the 21 with genetic diseases had suspected anomalies prenatally, compared with 33 (56%) of 59 with negative results. Among fetuses with suspected anomalies, genetic diseases were 4.5 times more common in those with multiple anomalies and 6.7 times more common in those with anomalies of the extremities compared to those with negative results. Had the genetic diseases been diagnosed prenatally, clinical management would have been altered in 13 of 14. Conclusion:Critically ill infants with diagnostic genomic sequencing were more likely to have multiple anomalies and anomalies of the extremities on fetal imaging.Among almost all infants with suspected fetal anomalies and diagnostic genomic sequencing results, prenatal diagnosis would have likely altered clinical management. Key pointsWhat's already known about this topic? � Diagnostic yield for prenatal genetic testing varies by type of anomaly suspected.� Genomic sequencing can inform management of critically ill neonates.

Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis

“…Although they were included as pathogenic variants in this review, it is unlikely that they would have been judged so prospectively in the prenatal period due to the impact on bioinformatic interpretational criteria to assign pathogenicity 58 . The availability of these criteria will differ between prenatal and postnatal cohorts, making it more likely that such variant would be classified as VUS and potentially upgraded postnatally 59 .…”

Prenatal exomes and genomes – so much new and so much more to learn

“…23 Two studies compare results from sequencing on neonates to what could have been detected prenatally if we had more access to sequencing and better strategies to analyze the data and show that many conditions could be diagnosed earlier. 24,25 Moreover, at least one study showed that even for fetuses with no observable structural anomalies, P and LP variants can be detected. 26 While this can be concerning, it demonstrates how we can learn from other clinical settings where sequencing is done, and instills optimism about what future research will teach us about currently unknown prenatal presentations of genetic diseases.…”

“…Strategies for analyzing data, such as inheritance filtering, can limit the results obtained 23 . Two studies compare results from sequencing on neonates to what could have been detected prenatally if we had more access to sequencing and better strategies to analyze the data and show that many conditions could be diagnosed earlier 24,25 . Moreover, at least one study showed that even for fetuses with no observable structural anomalies, P and LP variants can be detected 26 .…”