Kidney development out of tune : Genetic and functional aspects of congenital renal anomalies

Abstract

This thesis is a small but important paragraph in the short history of genetics, which elucidates the genetic basis of congenital renal diseases. Genetic predisposition drives the development of congenital anomalies of the kidney and urinary tract, but the clinical variability and large genetic heterogeneity requires a sophisticated approach to detect the genetic causes. In this thesis we sequenced 208 genes suspected to be involved in CAKUT in 453 patients with CAKUT, in order to detect genetic variants that are likely to disrupt gene function and lead to CAKUT. We identified multiple rare genetic variants that are predicted to disrupt the function of their corresponding gene. However, the results of a statistical analysis suggest that rare genetic variants in these tested genes are not more frequent in patients in comparison to healthy individuals. This suggests that none of these genes plays a major role in the development of CAKUT. It could be that variants in other genes may have a bigger effect on the risk of developing CAKUT, or that the risk of CAKUT depends on a combination of multiple genetic factors with a small effect and a number of environmental factors. Therefore, future investigations should test the role of all genes in CAKUT as well as environmental factors using even more patients with CAKUT.

We also present two individual patients with a unique combination of symptoms that has not been reported in the literature before. We describe the first application of whole genome sequencing in a patient with kidney disease to identify the genetic cause, which resulted in the identification of variants in multiple genes that are functionally related to the phenotypes observed in the patient. In another patient we identified and characterized a single genetic mutation that completely stops the expression of an essential protein in the kidney and lung tissue. The mutation leads to a new multi-organ disorder observed in our patient, including interstitial lung disease and congenital nephrotic syndrome. This discovery enabled the use of genetic testing in our hospital for other newborns with similar symptoms, thereby facilitating an early diagnosis and enabling the risk estimation of having more affected offspring.

Further, we discuss the tools that are available to scientists today to unravel the function of newly identified genes and study the alterations in gene function that may be caused by such uncharacterized genetic variants. We performed functional characterization tests to elucidate the impact of the variants in a single gene detected in several CAKUT patients. Here, we provide experimental evidence suggesting that the variants exert disruptive effects on, at least, one of the functions of the gene. Our results open a big question about the possibility of microscopic, hair-like structures on eukaryotic cells, called cilia, having an effect on the development of CAKUT.