Prenatal Versus Postnatal Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations

Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that diagnosed in the postnatal period.

A Multitubular Kidney-on-Chip to Decipher Pathophysiological Mechanisms in Renal Cystic Diseases

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major renal pathology provoked by the deletion of PKD1 or PKD2 genes leading to local renal tubule dilation followed by the formation of numerous cysts, ending up with renal failure in adulthood. In vivo, renal tubules are tightly packed, so that dilating tubules and expanding cysts may have mechanical influence on adjacent tubules. To decipher the role of this coupling between adjacent tubules, we developed a kidney-on-chip reproducing parallel networks of tightly packed tubes. This original microdevice is composed of cylindrical hollow tubes of physiological dimensions, parallel and closely packed with 100–200 μm spacing, embedded in a collagen I matrix. These multitubular systems were properly colonized by different types of renal cells with long-term survival, up to 2 months. While no significant tube dilation over time was observed with Madin-Darby Canine Kidney (MDCK) cells, wild-type mouse proximal tubule (PCT) cells, or with PCT Pkd1+/- cells (with only one functional Pkd1 allele), we observed a typical 1.5-fold increase in tube diameter with isogenic PCT Pkd1-/- cells, an ADPKD cellular model. This tube dilation was associated with an increased cell proliferation, as well as a decrease in F-actin stress fibers density along the tube axis. With this kidney-on-chip model, we also observed that for larger tube spacing, PCT Pkd1-/- tube deformations were not spatially correlated with adjacent tubes whereas for shorter spacing, tube deformations were increased between adjacent tubes. Our device reveals the interplay between tightly packed renal tubes, constituting a pioneering tool well-adapted to further study kidney pathophysiology.

Renal cystic diseases during the perinatal and neonatal period

Renal cystic diseases are a clinically and genetically diverse group of renal diseases that can manifest in utero, infancy, or throughout childhood and adulthood. These diseases may be unilateral or bilateral with a single cyst or multiple cysts, or with increased echogenicity of the renal cortex without macroscopic cysts. Certain cystic renal diseases are life-threatening, with many developing chronic kidney and hepatic disease if not recognized early enough. Therefore, due to the prevalence and life-altering complications of this specific group of diseases in vulnerable populations, it is crucial for clinicians and healthcare providers to have an overall understanding of cystic diseases and how to pre-emptively detect and manage these conditions. In this review, we discuss in detail the epidemiology, genetics and pathophysiology, diagnosis, presentation, and management of numerous genetic and sporadic renal cystic diseases, such as polycystic kidney disease, multicystic dysplastic kidney, and calyceal diverticula, with an emphasis on prenatal care and pregnancy counseling.

Renal cystic diseases and ciliopathies

Inherited renal cystic diseases comprise a spectrum of disorders that are typically characterized by dysfunction of the so-called cilia. These hair-like cellular appendages are involved in numerous cellular signalling processes. During development, cilia are important for the development of the left–right axis and for the establishment of cell polarity. Consequently, depending on the specific nature of the underlying ciliary defect, renal cystic diseases can be associated with a large spectrum of other organ manifestations, including congenital heart disease, retinopathy, polydactyly, and hepatic abnormalities, such as ductal plate malformation. Based on clustering of such symptoms, specific clinical syndromes, such as nephronophthisis, Bardet–Biedl syndrome, Joubert syndrome, and the various forms of polycystic kidney diseases, have been assigned. Subsequent genetic investigations have shown that these clinical distinctions are not necessarily consistent with the underlying genetic alterations, so that, for example, genes initially associated with Joubert syndrome can phenocopy autosomal recessive polycystic kidney disease. Thus, identification of the genetic cause can inform the clinical management to assess for potentially involved organ manifestations.