High-throughput mutation analysis for known and novel single-gene causes of kidney stones and related disorders

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Kidney stone disease comprises nephrolithiasis (NL) and nephrocalcinosis (NC). NL and NC are highly prevalent conditions in the general population (~10%) associated with significant morbidity and progression to chronic kidney disease (CKD). Its etiology is multifactorial with an environmental and a genetic component. Although the heritability has been estimated to 56% and more than 30 monogenic causes have been identified, the genetic basis of NL/NC remains largely unknown. Furthermore, for most patients with NL/NC, mutation analysis in causative genes has not been accessible so far, despite the fact that knowledge of the molecular cause of NL/NC may have important consequences for prognosis, prophylaxis and/or treatment. We hypothesize that the fraction of monogenic causes to the overall population of kidney stone formers is significantly higher than generally assumed. We recently developed a novel high-throughput mutation analysis approach that allows to simultaneously examine multiple genes in multiple individuals at very low cost. In a pilot-study we demonstrated the power of the technique in 268 unrelated patients with NL/NC. We thereby identified the molecular cause in 15% (40/268), further suggesting that the role of single-gene causes in NL/NC is indeed underestimated. With this proposal we aim to investigate two main goals: 1) Determination of the prevalence of >30 known monogenic causes in a clinically well-defined cohort of ~600 individuals with NL/NC, as well as characterizing genotype-phenotype correlations, related to age-of-onset and manifestation of CKD. 2) Identification of novel disease genes by whole exome/genome sequencing AND candidate gene analysis in subjects without prior findings in known genes. Implementation of this proposal will broaden the knowledge of the molecular basis of NL/NC. By identification of new disease mechanisms, this project may contribute to develop novel therapeutic targets and help to establish a more personalized treatment.