Facilitating personalized medicine of monogenic stone patients by genetic characterization Next generation sequencing (NGS), including employing a targeted (t)NGS panel of known and candidate genes, is highlighting that severe, inherited forms of urinary stone disease (USD) are more common than previously appreciated, with ~40 genes now implicated. These monogenic USD are at the forefront of the application of personalized medicine in nephrology. Treatments can target enzymes/mRNAs encoding key steps in the defective metabolic pathway that lead to accumulation of harmful intermediates or via chaperone treatments to help fold and correctly traffic the mutated proteins. Genic and allelic information is increasingly a prerequisite for involvement in these targeted clinical trials. Over the past 10 years, the Rare Kidney Stone Consortium (RKSC) has focused on recruiting and characterizing patient populations with monogenic USD with the aims to understand the natural history of the disorders, conduct genotype/phenotype studies, and categorize patients for clinical studies. This initially involved Sanger sequencing but more recently tNGS with a ~100 gene panel. As part of this screening, patients presumed to have either primary hyperoxaluria (PH) or Dent disease (two common USD), but without mutations in the canonical genes for these disorders by Sanger sequencing, were screened on the panel. Out of 297 analyzed patients, a monogenic cause was detected in 30 cases (10.1%), with mutations identified in 11 different genes. In the past year, all RKSC recruited patients have been primarily genetically screened employing this tNGS approach and of 102 families screened 33 (32.4%) have been genetically resolved with 8 different genes identified. Interestingly, in ~15% of cases genetic complexity was identified with an additional likely pathogenic variant in a second monogenic gene. Unfortunately, funding for the RKSC was recently lost but we plan to keep the consortium intact and here propose to genetically characterize monogenic USD recruited through the RKSC groups, primarily to identify patients for inclusion in clinical trials. The proposal has two specific aims: 1. Genotype patients with a phenotype consistent with a monogenic form of nephrolithiasis or nephrocalcinosis using global NGS approaches and 2. Characterize and analyze the array of variants beyond the causative gene in monogenic stone patients. The project has co-PIs, one an expert in clinical and biochemical aspects of USD (Dr. Lieske), and one an expert in the genetics of monogenic kidney diseases (Dr. Harris). Tested tNGS approached will be employed along with a developed and proven bioinformatics pipeline to identify likely causative variants. These results will be returned to the referring physician, with safeguards of counseling and variant conformation, to provide diagnostic information, to allow personalized treatment, and encourage clinical trial recruitment. The accumulated knowledge of gene variants and variant combinations derived for the study will allow for better understanding of these diseases and provide insights into genetic factors causing phenotypic modification.
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