Investigation into the genetics of fetal congenital lymphatic anomalies

Objective Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development and often present in utero as pleural effusion, chylothorax, nuchal and soft tissue edema, ascites, or hydrops. Many LAs are caused by single nucleotide variants, which are not detected on routine prenatal testing. Methods Demographic data were compared between two subcohorts, those with clinically significant fetal edema (CSFE) and isolated fetal edema. A targeted variant analysis of LA genes was performed using American College of Medical Genetics criteria on whole exome sequencing (WES) data generated for 71 fetal edema cases who remained undiagnosed after standard workup. Results CSFE cases had poor outcomes, including preterm delivery, demise, and maternal preeclampsia. Pathogenic and likely pathogenic variants were identified in 7% (5/71) of cases, including variants in RASopathy genes, RASA1, SOS1, PTPN11, and a novel PIEZO1 variant. Variants of uncertain significance (VOUS) were identified in 45% (32/71) of cases. In CSFEs, VOUS were found in CELSR1, EPHB4, TIE1, PIEZO1, ITGA9, RASopathy genes, SOS1, SOS2, and RAF1. Conclusions WES identified pathogenic and likely pathogenic variants and VOUS in LA genes in 51% of fetal edema cases, supporting WES and expanded hydrops panels in cases of idiopathic fetal hydrops and fluid collections. Key points What's known on this topic? Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development. Variants in several genes are known to cause LAs though many of variants remain unknown. The full contribution of LA genes to fetal hydrops and nuchal edema remains unknown. What does the study add? The study identifies novel likely pathogenic variants and variants of uncertain significance via whole exome sequencing and analysis of genes associated with LAs. Identified variants may improve diagnosis of fetal LAs among otherwise idiopathic fetal hydrops cases.