Dr. Kristen Gibson

Supervisor(s): Dr. Matthew Sampson
Award: KRESCENT Post-Doctoral Fellowship
Institution: Boston Children's Hospital, MA
Year: 2025-2028
Project Title: Transcriptome aided diagnosis of nephrotic syndromes
Topic(s): Genetics, Clinical research

Biography

Dr. Kristen Gibson is a Post-Doctoral Fellow in the Division of Nephrology at Boston Children’s Hospital and an affiliate member of the Broad Institute of MIT and Harvard. She earned her PhD in Medical Genetics from the University of British Columbia, where her research focused on genetic and circulating biomarkers in pediatric primary systemic vasculitis. Now working in the laboratory of Dr. Matthew Sampson, Dr. Gibson applies multi-omic approaches to improve the diagnostic utility of genome sequencing and elucidate genetic causes and risk factors for pediatric nephrotic syndrome. Her research aims to advance precision medicine for rare kidney diseases by integrating genomic data with clinical and molecular phenotypes.

Lay Summary

Nephrotic syndrome (NS) is a rare but significant chronic kidney condition, affecting approximately 2 in 100,000 children annually in Canada. Despite its rarity, it is one of the most common disorders managed by pediatric nephrologists. NS occurs when damage to the kidney’s filtering units, the glomeruli, impairs their ability to remove waste and excess water from the blood. This leads to excessive protein loss in the urine, which, if prolonged, can cause permanent kidney damage, kidney failure, and the need for a transplant.

To date, over 70 known genes can harbor mutations that can cause NS (“monogenic NS”). By performing genetic testing in the clinic, doctors can diagnose children with monogenic NS. This is important because children with monogenic NS are managed and treated differently, for example by not giving them immunosuppressant medications that will never work. Currently, most patients with NS who undergo genetic testing will not be found to have a disease causing genetic change (“mutation”). Indeed, some of these children with NS truly do not have a genetic cause. However, our central belief driving this proposal is that a substantial number of children with NS in fact do have a monogenic form of their disease, but we are missing this diagnosis using only our standard clinical approach of DNA sequencing alone. We believe that the majority of these “misses” occur because the disease causing mutation is in the non-coding part of the genome. Non-coding variants that are disease causing most often cause problems through dysregulation of the associated gene. This can be by changing a gene’s overall expression or, through splicing, by altering which coding regions of the gene are included. However, it is very difficult to judge a non-coding variant as disease-causing by just examining the DNA changes alone.

Fortunately, a growing body of work is demonstrating that incorporating gene expression data (“transcriptome”) of the cells and tissues affected by a specific disease into a genetic diagnostic pipeline can greatly increase our ability to make a definitive diagnosis. This is because we can follow a plan to first try to detect rare, pathogenic gene expression changes and, with this information, go back to the DNA sequence to discover the specific, functional genetic variant that is causing this problem. Studies outside of the kidney have found that following this plan - incorporating gene expression information in a genetic diagnosis pipeline - increases diagnostic rates 8–36% over DNA sequencing alone. Here, we propose to test the overall hypothesis that a “transcriptome-first” diagnostic strategy for patients with NS will empower us to discover patients with a monogenic form of their disease that we would have not detected otherwise. Because we know that the pathogenesis of focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) can be due to functional changes in resident kidney and/or immune cells, we plan to study both cell types. In Aim 1, we will use existing computational methods on gene expression data from kidney biopsies of 166 patients in the NEPTUNE study with FSGS and MCD to discover pathogenic gene expression abnormalities. We will then link these changes back to these same patients existing genome sequencing data to pinpoint the genetic change causing the disease.

In Aim 2, we will follow the same plan, except that we will be searching for pathogenic gene expression changes in the circulating immune cells of 720 patients in the CureGN study with FSGS and MCD and then linking them back to DNA changes. This research will quantify the utility of incorporating gene expression data to help diagnose NS patients with genetic forms of their disease. We expect to discover both novel causal variants in known genes, novel disease-causing genes, and/or novel genome-biology driving monogenic architecture of nephrotic syndrome.