The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study

Abstract

Objective To study the value of exome sequencing (ES) in severe pleural effusion with non-immune hydrops fetalis (NIHF) that underwent thoracoamniotic shunt (TAS). Methods It was a retrospective study of NIHF that underwent TAS between 2012 and 2020 at Shanghai First Maternity and Infant Hospital. After a detailed assessment, NIHF cases with aneuploidies, infections, and structural anomalies were excluded, and TAS was offered to cases with severe pleural effusion. Quantitative fluorescence polymerase chain reaction (QF-PCR) was conducted to exclude Trisomy 21, 18 and 13 before fetal therapy, and chromosomal microarray analysis (CMA) was offered to all the cases. Before 2019, ES was retrospectively performed using stored fetal DNA extracted from prenatal samples; from 2019 onwards, ES was discussed and offered before intrauterine therapies. Results A total of 18 NIHF cases underwent TAS with negative CMA and continuing pregnancy were included. Fetal hydrops was relieved in 16 cases (88.9%). The median gestational ages at intervention and at delivery were 31.2 (22.0~33.1) weeks and 34.3 (29.7~38.6) weeks, respectively. The neonatal survival rate was 72.2% (13/18) and no causative gene variants were identified from ES in any survivors. Pathogenic or likely pathogenic variants were detected in 3 out of 5 neonatal deaths. If rapid ES could have been available to guide fetal therapy, the neonatal survival rate after TAS would have increased from 72.2% to 86.7%. Conclusions Single gene disorders was one of the major causes of perinatal death in NIHF cases that underwent fetal therapy. Prenatal rapid exome sequencing may be of good promise in NIHF to exploring precise etiology and guide fetal therapy.

Hydrops fetalis: Incidence, Etiologies, Management Strategies, and Outcomes

“…While currently more expensive than these modalities, exome sequencing may nonetheless represent a more timely and overall more cost-effective approach. 37,38 It should be noted that clinical judgement should continue to direct genetic testing as exome does not diagnose all known genetic etiologies of hydrops fetalis such as myotonic dystrophy, which is caused by a short tandem repeat expansion, or genetic changes due to deep intronic variants such as cryptic splice changes. 39 In addition to genetic testing, amniotic fluid analysis for glycosaminoglycans and lysosomal enzymatic activity may aid in the diagnosis of lysosomal storage diseases or disambiguation of variants of uncertain significance in related genes.…”