Is Involved in Congenital Chylothorax.

Besides visceral heterotaxia, null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of mutant mouse embryos revealed about 20% of embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of in congenital lymphatic anomalies, including CCTs.