BACKGROUND AND PURPOSE: 

• Next generation sequencing methods, such as targeted gene panels and exome sequencing, are increasingly used in prenatal diagnosis, but which is better at detecting abnormalities is unknown 
• Norton et al. (AJOG, 2021) compared the diagnostic yield of exome sequencing vs gene panels in fetuses with nonimmune hydrops fetalis (NIHF) 

METHODS: 

• Secondary analysis of a cohort study 
• Population 
  • Pregnancies with features of NIHF 
• Exposures 
  • Exome sequencing 
  • Simulated use of targeted gene panels for prenatal evaluation of NIHF or for specific disorders associated with NIHF 
• Primary outcome 
  • Proportion of all genetic variants discovered through exome sequencing that would have been identified if a targeted gene panel had been used instead 
• Secondary outcomes 
  • Proportion of genetic variants that would have been identified stratified by type of targeted gene panel  
    • e.g general NIHF, RASopathy, or metabolic 
  • Percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes 

RESULTS: 

• 127 pregnancies 
• Exome sequencing  
  • Pathogenic or likely pathogenic variant: 29% of cases in a total of 29 genes 
  • Variant of uncertain significance with strong suspicion for clinical relevance: 9% of cases 
• Panels offered 
  • Median number of genes offered with targeted NIHF commercial gene panels: 22 (range 11 to 148) 
• Had a targeted gene panel been used instead of exome sequencing 
  • 45 to 52% of the 29 genes identified in NIHF exome cohort would have been sequenced 
  • 51 to 62% of the pathogenic variants would have been detected 
• The largest NIHF targeted gene panel would have had a diagnostic yield of 18% as compared to 29% with exome sequencing 
• The exome sequencing platform provided coverage for all of the exons on the commercial targeted gene panels 

CONCLUSION: 

• Prenatal exome sequencing performed better than simulated targeted gene panel testing for nonimmune hydrops fetalis 
• The authors suggest that for detecting genetically heterogeneous disorders, exome sequencing is superior to targeted gene panels 

Learn More – Primary Sources: 

Exome sequencing versus targeted gene panels for the evaluation of nonimmune hydrops fetalis 

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Can Whole-Exome Sequencing Help Diagnose Otherwise Unexplained Fetal Structural Anomalies?