Rare diseases (RD), generally defined by an incidence of less than 1:2000, affect about 3-6% of the population. To date, over 600 different genetic kidney diseases have been identified. Most of them with the exception of autosomal dominant polycystic kidney disease (ADPKD) are rare to ultrarare disorders. Due to their rarity and often genetic heterogeneity, analysis is difficult and diagnosis is frequently delayed. Clinically, (rare) kidney diseases (RKD) are mainly divided into the following categories: Congenital or developmental kidney and urogenital tract malformations, electrolytes or metabolic disorder, glomerular disease, secondary renal, hereditary renal cancer syndromes, or tubulointerstitial kidney disease. Steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS), are leading causes of end-stage renal disease (ESRD) in children, adolescents, and adults. Although several SRNS genes could be identified mostly in younger children, the genetic basis of SRNS/FSGS in adolescents and adults is far from being completely understood. Reliable discrimination of genetic versus non-genetic forms is an imperative as the identification of monogenic rare kidney disease has numerous implications in a precision medicine setting. Currently, the predominant application of short-read based sequencing techniques results in preferential detection of point mutations and small-sized deletions/insertions while larger structural aberrations (large deletions/insertions), gene rearrangements, and mutations in homologous or repetitive regions frequently escape detection. This project combines short-read based high throughput next-generation sequencing (GPS/WES/WGS) with unparalleled structural variant analyses to overcome previous limitations in genetic analyses. Clinically relevant examples, that such structural variants (SV) are important in rare kidney diseases, are complement activation gene cluster (RCA; chromosome1q32) in atypical haemolytic uremic syndrome (aHUS) as well as the deletion of the chloride channel ClC-Kb associated with Bartter syndrome type 3. The major goal of this project is to unravel the genetic basis of genetic forms of RKD like SRNS/FSGS, aHUS, and tubulopathies and to define a pipeline for the molecular genetic analyses of rare kidney diseases as a best-practice clinical routine at the University Hospital of Cologne. Specifically, my aim was to perform profound genome analyses using biosamples from a cohort of paediatric and adult SRNS/FSGS patients, that have been collected over the last years and integrate this with already existing genetic data. By a comprehensive genomic approach, we aim to improve the diagnostics of chronic kidney disease, enhance our
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understanding of the underlying pathomechanisms, and contribute to practice-changing discoveries by precision diagnostics, that allow individualized therapies
