Genetic diseases underlying a spectrum of fetal effusions

Nonimmune hydrops fetalis is well understood to be heterogenous and the common endpoint of many genetic diseases. However, less is known about the prevalence and presenting features of genetic diseases that underlie other types of fetal effusions such as single effusions, leaving uncertainty in clinical practice about optimal approaches to testing and counseling for these pregnancies. We aimed to determine the diagnostic yield of exome sequencing by type of fetal effusion and presence of concurrent structural abnormalities and to identify the unique presenting features of underlying genetic diseases.

We conducted a prospective cohort study of pregnancies with nonimmune hydrops fetalis and other fetal effusions, with participants enrolled from across the United States. Inclusion criteria were nondiagnostic results of chromosomal microarray and/or karyotype and the presence of at least 1 fetal effusion, including nuchal translucency ≥3.5 mm, cystic hygroma, pleural effusion, pericardial effusion, ascites, and/or skin edema. Exome sequencing was performed by our institution's Clinical Laboratory Improvement Amendments-approved laboratory and results were returned to participants and their providers. Detailed fetal phenotypic data were ascertained and used to inform genetic variant interpretation, including fetal imaging findings (ultrasound, magnetic resonance imaging, and echocardiogram), pathology reports, and laboratory reports. Pregnancies with a variant or variants classified as pathogenic or likely pathogenic were considered diagnostic or positive. The primary outcome was the diagnostic yield of exome sequencing by the type of fetal effusion, with and without concurrent structural abnormalities. Secondary outcomes were the types of fetal effusions observed by category of genetic disease.

In all, 118 pregnancies with nonimmune hydrops fetalis and other effusions underwent exome sequencing and 23% (27/118) had positive (diagnostic) findings. Pregnancies with nonimmune hydrops fetalis with and without concurrent structural abnormalities had diagnostic yields of 21% (9/42) and 40% (6/15), respectively (P=.15). Single effusions such as pleural effusion with and without concurrent structural abnormalities had diagnostic yields of 23% (6/26) and 17% (1/6), respectively (P=.61). The diagnostic yield for increased nuchal translucency or cystic hygroma was significantly greater for pregnancies with concurrent structural abnormalities (42%, 5/12) compared to those without (0%, 0/17, P<.01). We further observed numerous patterns in terms of how genetic diseases present in utero, such as RASopathies and musculoskeletal disorders demonstrating all types of effusions, while other disorders marked by neurodevelopmental delays after birth demonstrated all types of effusions except for nonimmune hydrops fetalis.

The diagnostic yield of exome sequencing was high across all types of effusions including single effusions with and without concurrent structural abnormalities, with the exception of isolated increased nuchal translucency or cystic hygroma. Furthermore, we observed numerous patterns in terms of how genetic diseases present in utero with fetal effusions. These findings contribute important information for counseling and clinical management, highlight the utility of exome sequencing for fetal effusions beyond nonimmune hydrops fetalis, and inform accurate results of phenotype-driven tests such as exome sequencing.