De novo heterozygous missense variants inCELSR1as cause of fetal pleural effusions and progressive fetal hydrops

Abstract

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whomde novoheterozygous missense variants in the planar cell polarity geneCELSR1were detected using exome sequencing. Using several in vitro assays, we show that theCELSR1p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rareCELSR1variants could be a possible cause of fetal hydrops.