Purpose Chromosomal microarray (CMA) is recommended in the diagnostic evaluation of cases with fetal structural anomalies when invasive testing is pursued. However, the utility of CMA for nonimmune hydrops fetalis (NIHF) specifically is not well known. Our objective was to describe the overall yield of CMA in the diagnostic evaluation of NIHF, comparing isolated cases to those with concurrent structural anomalies. Methods This was a retrospective cohort study of all prenatally diagnosed NIHF cases evaluated at the University of California, San Francisco from 2008 to 2018. NIHF due to twin‐twin transfusion syndrome was excluded. Results There were 131 cases of prenatally diagnosed NIHF. In 43/44 cases with a CMA performed, results were categorized as normal or likely benign. One case was found on CMA to have a large pathogenic duplication of 21p11.2q22.3, which could have been detected by karyotype and was consistent with a diagnosis of Down syndrome. There was no incremental yield demonstrated for CMA over karyotype. Conclusions Among a cohort of prenatally diagnosed NIHF cases, CMA did not identify any copy number variants beyond those detectable by karyotype, and the vast majority of CMAs were normal. These results suggest that CMA has low diagnostic utility for NIHF.

We sought to determine the yield of whole exome sequencing (WES) in determining the genetic etiology of fetal pleural effusions. STUDY DESIGN: We examined a retrospective cohort series of all cases of fetal pleural effusions visualized by prenatal ultrasound at a single center between May 1, 2016 and May 31, 2017. Prenatal and postnatal medical records were examined for clinical presentation and diagnostic workup. Fetal pleural effusions attributed to twin sharing, red cell alloimmunization, or structural anomalies were excluded, as were cases with a genetic diagnosis confirmed by karyotype or microarray analysis. The remaining cases were offered WES. WES was performed on cases submitted for either clinical sequencing or sequencing under the Baylor-Hopkins Center for Mendelian Genomics' research sequencing platform. RESULTS: Twenty-four fetuses with pleural effusions were evaluated by prenatal ultrasound. Eleven cases (45.8%) were excluded due to twin-transfusion (3 cases), twin anemia polycythemia sequence (1 case), Rh disease (2 cases), congenital diaphragmatic hernia (2 cases), cystic pulmonary airway malformation (1 case), and fetal teratoma (2 cases). Six additional cases (25%) were excluded due to diagnoses of monosomy X (4 cases), trisomy 21 (1 case), and terminal 7q36 deletion/7p22 duplication (1 case). Of the remaining 7 cases, 5 underwent WES, including 3 parent-proband trios and 2 parent-proband-affected sibling quads. We identified a pathogenic variant in 1 case, a likely pathogenic variant in a second case, and 3 cases with variants of unknown significance with potential for reclassification based on expansion of phenotype (see table). CONCLUSION: Following standard clinical evaluations, a causative etiology remained unknown in 29.2% of prenatally diagnosed pleural effusions. In the present series, WES identified a pathogenic variant in 20% of such cases. Additional variants identified by WES require validation studies for confirmation. WES should be considered in cases of fetal pleural effusions when the standard evaluation is not diagnostic.