Delineating the genetic causes of non-immune hydrops fetalis by whole-exome sequencing: a pilot series

Prenatal diagnosis by whole-exome sequencing (WES) may help to decipher genetic causes in structural abnormalities detected by fetal ultrasound. Non-immune hydrops fetalis (NIHF) is a disease spectrum with heterogeneous etiologies. In this study we did a retrospective study on our pilot series (n = 11) of NIHF underwent WES and summarised the pregnancy outcomes. Each case we performed detailed sonographic examination for anasarca, virology profile, karyotyping, chromosomal microarray analysis in addition to WES, either prenatal or postnatal. From December 2019 to July 2022, 11 cases were analysed by trio-WES due to the obscure cause of the pathologic fluid accumulations in fetal compartments. We used the American College of Medical Genetics and Genomics (ACMG) to classify variants. Of the 11 fetuses, nine (82%) had definite molecular diagnosis, including three with musculoskeletal disorders (33%), three with lymphatic disorder (33%) and two with syndromic disorder (22%). All recurrent cases (2/2, 100%) and those who received fetal therapy (3/3, 100%) have definite molecular diagnosis. Two survived fetuses were diagnosed at first and third trimester, respectively. Three fetuses had neonatal death and six couples terminated the pregnancies. Two novel founder variants were found (HSPG2 and BBS2). Trio-WES is an effective tool to ascertain genetic diagnosis for NIHF cases and would discover more novel causative genes to match the exhibited prenatal phenotypes.