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Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.

Chronic renal failure and end stage renal disease (ESRD) can be life-threatening conditions. In a significant number of cases with ESRD the primary cause l is a congenital anomaly of the kidney and/or urinary tract (CAKUT). Vesico-ureteral reflux (VUR) is the most common of the CAKUT spectrum. The studies in this thesis focus on isolated VUR. Although most children grow out of VUR without serious morbidity, a subset has associated complications. Together these account for 15% of ESRD in Dutch children. An autosomal dominant inheritance pattern with reduced penetrance is seen in some VUR families. Other segregation patterns have also been described, but for most cases a multifactorial etiology is most likely. Disruption of ureter budding in mouse embryos has been shown to lead to CAKUT. Genes involved in this budding process are therefore considered to be candidate genes for VUR susceptibility. The studies in this thesis were aimed at identifying genetic risk factors for VUR and/or CAKUT. Chapter 2 presents a literature study regarding the relationship between prenatally detected hydronephrosis (PNH) and postnatal VUR. In 15% of the patients with PNH primary VUR was detected, approximately 35% had other urogenital anomalies and in 50% postnatal examinations were normal. To explore whether we could provide clinical evidence for a new hypothesis on a contributory constitutional factor to VUR predisposition, and therefore on VUR genetics, we evaluated joint hypermobility in 50 VUR patients (chapter 3). The results of this study suggest that patients with hypermobile joints may have underlying systemic laxity that might in turn contribute to VUR. In chapters 4, 5 and 6 we investigated candidate genes in the ureter budding process for their role in VUR development with varied genetic approaches. We studied a syndromal patient with severe VUR who had a complex chromosomal aberration disturbing the ROBO2 gene. ROBO2 is a protein known to have a role in the ureter budding pathway. This led us to search for mutations in this gene in 124 VUR patients. Indeed mutations were detected in two familial cases. In four families we performed a linkage study, that focused on a subset of genes in the ureter budding process and other candidate regions. We could significantly exclude a role for the majority of genes under investigation. We performed an association study of common SNPs in 44 genes in the ureter budding pathway in > 400 Dutch VUR cases and > 1400 controls. None of the SNPs were significantly associated to VUR. Common SNPs in four ureter budding genes (GREM1, EYA1, ROBO2 and UPK3A) did show a trend towards association. In a subset of VUR patients with duplex collecting systems we identified 3 patients with mutations in UPK3A that possibly contribute to their phenotype. In chapter 7 we investigated patients with renal adysplasia, another part of the CAKUT spectrum. We investigated a gene known to be involved in renal adysplasia in other populations (UPK3A) and a new candidate gene (FGF7). We studied 19 patients and identified the first known stop-mutation in UPK3A.

The work in this thesis makes the case for a genetics-first approach in CKD. Though there is a high prevalence of monogenic kidney disease (MGKD), it is underdiagnosed in daily practice. This while an adequate MGKD diagnosis provides patients with life-long improvements in care and well-being. Next to the direct impact on patients, the outcomes of genetic testing increase knowledge on disease processes. More knowledge on MGKD will allow for the identification of more MGKD patients and the improvement of reproductive care.