What are the novel findings of this work?In this study of 114 cases that underwent termination of pregnancy following the detection of a major central nervous system anomaly, chromosomal microarray analysis (CMA) detected causative copy-number variants (CNVs) in 10% of fetuses. Among 86 CMA-negative cases, exome sequencing (ES) detected causative sequence variants in 44%. The ES bioinformatics pipeline also detected 13 of the causative and previously known non-causative CNVs. What are the clinical implications of this work?Our data suggest that ES could be considered as a first-tier clinical diagnostic test in the prenatal diagnosis of fetuses with major CNS anomalies, as it can detect both sequence variants and CNVs.

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Key points What's already known about this topic? Genetic lymphatic disorders are a common cause of non‐immune hydrops fetalis, with PIEZO1 being one of the more recently established disease‐causing genes. What does this study add? Disease‐causing PIEZO1 variants have mostly been reported as single nucleotide variants or small indels. We report on a fetus with compound heterozygous deletions within and including PIEZO1. The deletions were not detected by chromosomal microarray (CMA). This case highlights the value of exome sequencing in detecting copy number variants that are below CMA resolution.

The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post‐translational insertion of tail‐anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss‐of‐function and one previously reported recurrent EMC10 variants. This report expands the molecular and clinical spectrum of EMC10 deficiency, provides a comprehensive dysmorphological assessment and highlights an overlap between the clinical features of EMC10‐and EMC1‐related disease.