Over the past 10 years, next-generation sequencing methodologies have rapidly matured into an inexpensive, reliable, widely available, and highly efficient set of tools to do genomic research. Our laboratory pioneered the use of one of these ground-breaking methodologies, known as whole-exome sequencing (WES), which allows for high throughput sequencing of all of the genome's protein coding regions (exons). WES has several advantages over whole-genome sequencing: it is considerably cheaper since it does not include 99% of the genome that does not encode proteins, data interpretation is simpler because one can rely on amino acid conservation to prioritize mutations, and it focuses on data where the vast majority of mutations causing Mendelian diseases cluster. The emergence of WES (and WGS) has had a major impact on genetic research because for the first time, groups of isolated probands with similar phenotypes can be used as a cohort for gene discovery projects. We set out to use this technology to identify novel disease-causing genes in two large cohorts of patients with rare pediatric kidney disease, namely atypical hemolytic-uremic syndrome (aHUS) and Dent's disease (DD).
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