The Clinical Utility of Sequence-Based Genetic Testing for Fetal Edema Following Non-Diagnostic Microarray Results: A Population-Based Cohort Study.

OBJECTIVE

Ultrasound findings of fetal edema may provide early evidence of a genetic disorder. Our objective was to evaluate the frequency and diagnostic yield of sequencing in a selected population after a non-diagnostic microarray result for fetal edema.

METHOD: Fetal edema (nuchal translucency > 3.5 mm, cystic hygroma, hydrops, other types) cases referred for genetic testing (2014-2022) were identified in our laboratory information system. Chart review confirmed associated ultrasound findings, findings from other imaging or pathology, multidisciplinary review, and genetic test utilization. Descriptive analyses determined diagnostic yields.

RESULTS

There were 114 fetal edema cases with a non-diagnostic microarray result. Multidisciplinary review occurred in 79 (83%) cases, with targeted genes, gene panels, and/or exomes performed in 51 (54%) cases based on clinical assessment. Diagnoses were made in 17 (34%, with 59% providing a recurrence risk of ≥ 25%). RASopathy testing and exomes (with selective criteria) resulted in diagnostic yields of 18.5% and 41.2%, respectively. The highest diagnostic yields were in cases with fetal hydrops and other types of fetal edema (restricted to one body cavity).

CONCLUSION

Review of additional testing beyond CMA in this cohort did not attempt to assess the overall yield of sequencing; instead, the study used a selected approach in which cases of fetal edema underwent further testing beyond CMA. In cases with cystic hygroma or increased nuchal translucency, RASopathy panel sequencing provides a good diagnostic yield, and should be offered as standard of care with CMA. Correlation of new and developing prenatal and postnatal findings, along with multidisciplinary team review, may inform additional testing, counseling and pregnancy management options, and is particularly important to consider in cases presenting with non-immune fetal hydrops.