Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis.

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Pathogenic variants in PAX2 have previously been associated with renal coloboma syndrome. Here we present a novel variant c.68T>C associated with bilateral kidney agenesis, minimal change nephropathy, ureteropelvic junction obstruction, duplex kidney with hydronephrosis of upper pole system and bilateral kidney hypoplasia within the same family. Additionally, two family members were found to have optic nerve abnormalities further supporting the impact of the PAX2 variant. This is the first report of a PAX2 variant associated with bilateral kidney agenesis.

Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and decline of renal function. The clinical feasibility of a number of potential disease-modifying drugs is limited by systemic, adverse effects. We hypothesize that megalin, a multi-ligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects. Methods The cyst expression of various tubular markers including megalin and aquaporin 2 (AQP2) was analyzed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1RC/RC) at different postnatal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin. Results Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed a partial expression of megalin, expression of AQP2 or no expression of examined markers. Endocytic uptake of aprotinin was evident in megalin positive cysts, but only in those that remained connected to the renal tubular system. Conclusions Megalin expressing cysts were observed at all ages, but the proportion decreased with age possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease.