Diagnostic yield using whole-genome sequencing and in-silico panel of 281 genes associated with non-immune hydrops...

To investigate the diagnostic yield of clinical whole-genome sequencing (WGS) in prenatally diagnosed non-immune hydrops fetalis (NIHF).

This was a retrospective study of 23 fetuses with prenatally diagnosed NIHF, negative for trisomies and copy-number variants, referred for analysis by WGS with an in-silico panel of 281 genes associated with hydrops fetalis. Due to identification of a high proportion of causative variants in the HRAS gene in the main cohort, Sanger sequencing of HRAS was performed in a replication cohort, consisting of 24 additional fetuses with NIHF that were negative for trisomies and copy-number variants and had not undergone WGS.

Of the 23 fetuses in the main cohort, a molecular diagnosis was achieved in 12 (52.2%). Pathogenic or likely pathogenic variants were identified in seven genes: HRAS (n = 5), RIT1 (n = 2), FOXP3 (n = 1), GLB1 (n = 1), MAP2K1 (n = 1), PTPN11 (n = 1) and RASA1 (n = 1). The inheritance pattern of the 12 causative variants was autosomal dominant in 10 cases (HRAS, MAP2K1, PTPN11, RASA1, RIT1), autosomal recessive in one (GLB1) and X-linked recessive in one (FOXP3). Of the 24 fetuses in the replication cohort, a pathogenic variant in HRAS was identified in one, resulting in an overall frequency of causative HRAS variants of 12.8% (6/47) in our two cohorts.

We demonstrate a diagnostic yield of 52% with clinical WGS in NIHF using an in-silico panel of 281 genes. However, the high diagnostic yield may be attributed to the small sample size and possible over-representation of severe phenotypes in the included fetuses. Bearing in mind that chromosomal abnormalities were excluded in our cohorts, a detection rate of up to 75% is possible in prenatally diagnosed NIHF when WGS analysis includes calling of chromosomal aberrations. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.