Abstract: TH-PO0607
Transcriptome-First Approach to Diagnose Monogenic Nephrotic Syndrome
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Gibson, Kristen, Boston Children's Hospital, Boston, Massachusetts, United States
- Gomez, Alexis C., Boston Children's Hospital, Boston, Massachusetts, United States
- McNulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States
- Onuchic-Whitford, Ana C., Brigham and Women's Hospital, Boston, Massachusetts, United States
- Lee, Dongwon, Boston Children's Hospital, Boston, Massachusetts, United States
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
Background
Nephrotic syndrome (NS) is a rare glomerular disease that can lead to chronic kidney disease and, in some cases, end-stage renal failure. While more than 70 monogenic causes have been identified, most patients remain without a molecular diagnosis using current genome sequencing pipelines. This is partly due to the difficulty in interpreting variants within non-coding regions, especially intronic regions. A genetic diagnosis is essential for guiding clinical management and therapeutic decisions for patients with NS. Integrating transcriptomic data has been shown to improve diagnostic yield beyond genome sequencing alone, with reported increases of 8–36%. We hypothesized that incorporating RNA-sequencing (RNA-seq) into the diagnostic workflow would uncover previously unrecognized monogenic cases of NS.
Methods
We analyzed paired whole genome sequencing (WGS) and RNA-seq data from micro-dissected glomerular and tubular compartments of kidney biopsy samples of 82 pediatric patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). A transcriptome-first approach was employed using the Detection of RNA Outliers Pipeline (DROP). Aberrant gene expression and splicing events were identified among the 82 cases, followed by retrospective interrogation of WGS data for causal variation.
Results
Among 82 pediatric patients, 39 (48%) exhibited at least one aberrant expression event (median = 1; max = 68) and 71 (91%) showed evidence of at least one aberrantly spliced gene (median = 8; max = 114). This approach led to the identification of candidate monogenic causes in 5 patients (6%). Identified cases included known genes associated with kidney disease including chromodomain helicase binding DNA binding protein l like (CHD1L) and steroid sulfatase (STS), as well as novel candidate NS genes requiring further investigation.
Conclusion
These findings support the diagnostic value of integrating transcriptomic data into genetic evaluation for NS. This approach not only improves diagnostic rates but also highlights novel candidate genes, potentially expanding the landscape of monogenic NS.
Funding
- Private Foundation Support