Nephrotic Syndrome

Matthew G. Sampson, MD, MSCE

Assistant Professor of Pediatrics and Communicable Diseases Pediatrics-Nephrology

Benz Birth Defects Research Award and Charles Woodson
Interdisciplinary Award in Children’s Health $30,000

Discovery of Pathogenic Copy Number Variation in Nephrotic Syndrome


Nephrotic syndrome (NS) is a nonspecific kidney disorder characterized by a number of signs and can be associated with a series of complications that can affect an individual's health and quality of life. (NS) is a rare glomerular disease which reduces the ability of the kidneys to maintain a balance of certain substances in bloodstream. Normally, the kidneys should filter toxins out of the bloodstream and excrete them in the urine, but should keep red blood cells and protein in the bloodstream. In people with glomerular disease, red blood cells and protein may be excreted into the urine, while toxins may be retained. This can cause catastrophic complications and end stage renal disease (ESRD). The current taxonomy of NS based on histology or response to therapy does not reflect its underlying molecular basis. This hinders our ability to accurately predict the natural history and therapeutic response for each patient, and prevents the design of therapeutic regimens that target specific molecular abnormalities. We are thus challenged to devise strategies to define NS in mechanistic terms in order to treat this disease with the precision it needs. One method being successfully employed to molecularly dissect many human diseases is identification of genetic variation associated with a condition and derivation of functional insight by linking these variants to other genome-scale and clinical datasets. Using this approach, common and rare disease-associated variants, in coding and noncoding regions, have been discovered. This has spurred biomarker discovery, unravel disease mechanisms, and identified targets for therapeutic intervention; all resulting in advancements in patient care.

To achieve these goals for NS, Dr. Sampson's lab is using whole genome sequencing (WGS) to create a catalogue of genomic variation in 400 incident subjects enrolled in the prospective, observational, multicenter Nephrotic Syndrome Study Network (NEPTUNE). The lab is already revealing the pathogenic role of DNA sequence variation in patients by (1) identifying known harmful single nucleotide variants (SNV), (2) discovering novel NS-associated SNV, and (3) integrating their biosamples and clinical data to discover the clinical and mechanistic impact of these SNV. We now wish to extend this genomic inquiry by determining the prevalence and mechanism of pathogenicity of rare copy number variation (CNV) in NS.

Dr. Sampson and his team now need to task a computational analyst to the CNV discovery/analysis project being proposed. 100% of this award will be utilized for salary support of this individual. It is estimated that this project will take 50-75% of their effort. Over the next year, the output of this project will include at least one manuscript accepted to a moderate impact nephrology journal or genetics reporting the prevalence of rare CNVs in NS. Detailed analysis of our top novel CNVs should result in manuscript submission and publication within 24 months. This CNV project will complement the data and papers emerging from our current work on novel SNV genomic risk factors in NS. Together, Dr. Sampson believes that these publications and preliminary data will serve to make him competitive for an RO1 submission to the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) in June 2015 focusing on discovering and characterizing novel genomic risk factors for NS. At the same time, this data will help as Dr. Sampson explores applying concomitantly to other external resources (e.g. NephCure, American Society of Nephrology, Satellite Healthcare) for long-term funding of this project.