Abstract: SA-PO398
Genetic Variants in Basement Membrane Genes Are Enriched in Nephrotic Syndrome
Session Information
- Genetic Diseases of the Kidney - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Bierzynska, Agnieszka, University of Bristol, Bristol, Bristol, United Kingdom
- Sherwood, David R., Duke University, Durham, North Carolina, United States
- Barua, Moumita, Toronto General Hospital, Toronto, Ontario, Canada
- Welsh, Gavin Iain, University of Bristol, Bristol, Bristol, United Kingdom
- Saleem, Moin, University of Bristol, Bristol, Bristol, United Kingdom
- Lennon, Rachel, University of Manchester, Manchester, United Kingdom
Background
Basement membranes (BM) are essential for tissue formation and function. Core components include laminins, collagens and heparin proteoglycans. Genetic defects in BM components cause a spectrum of rare human diseases, however, recent large-scale genetic studies have shown that variants in BM genes associate with more prevalent disease including diabetic nephropathy. Whilst the role of core BM components have been linked to human disease, there are more BM components and interactors that are likely to have key roles in BM assembly and regulation. We hypothesised that BM integrity is key to kidney survival and that genetic variants in a wide spectrum of BM genes associate with disease. We aimed to identify genetic differences in BM genes between patients with nephrotic syndrome (NS) and controls.
Methods
We assembled a list of 110 genes, likely to be important for BM function. The list was derived from Gene Ontology classification, proteomic analyses of extracellular matrix, and functional screens in C. elegans. We used this list to screen 133 exome sequenced Caucasian patients with paediatric onset of NS. The frequency of detected single nucleotide variations (SNVs) in the cohort was compared with the general population (gnomAD controls, European non-Finnish). Randomly selected genes were also examined and used as control genes. Chi-squared test with Yates correction (2x2 contingency tables) was used.
Results
25 SNVs were found to be significantly over-represented in the NS patients when compared to controls. 16 of those had the minor allele frequency (MAF) over 2x higher than in the general population. The biggest MAF differences were found in HMCN2, SMOC1, LAMA5, MATN1, LAMA2 and ADAMTS16 genes. No SNVs were enriched in the control genes. Furthermore, we screened 50 genes (BM and other) known to cause NS and identified 5 candidates that caused a BM rupture phenotype in C. elegans and this frequency was approximately 20-fold higher than randomly selected genes.
Conclusion
Overall these findings support our hypothesis that BM integrity is key to long term kidney survival.