Genetic Landscape of Glomerular Diseases and FSGS among More than 50,000 People Genetically Tested for CKD

Background: Focal segmental glomerulosclerosis (FSGS) is a histologic feature that is characteristic of a variety of glomerular diseases (GD). Etiologies of FSGS can be genetic, environmental, or idiopathic. Genetic testing can directly identify the cause of disease; without it, the various forms can be indistinguishable. A recent study demonstrated the utility of genetic investigation to identify an underlying cause of FSGS, especially important given the heterogeneity and that most genetic subtypes are not responsive to steroid therapies. Here we investigate the landscape and contribution of FSGS-related genes in GD in a large cohort. Methods: A retrospective analysis of results from patients tested with a renal gene panel (the RensightTM test) May 2020 - July 2023 identified cases that: a) indicated a GD and/or an ICD-10 code in the N00-N08 range on the requisition form and/or b) had positive findings (1 pathogenic (P) or likely pathogenic (LP) variant in a gene associated with autosomal dominant or X-linked disease, or 2 P/LP variants or risk alleles in an autosomal recessive gene) in one of 35 FSGS-related genes. The proportion of P/LP variants in each gene and odds ratios of variants in the GD and non-GD groups were assessed. Results: Across 57205 individuals, 15490 had a positive test result, of which 49.9% (7737) were in one or more FSGS-related genes. Of the 35 FSGS-related genes queried, positive results were identified in 26. While APOL1 and COL4A3/4/5 were the most prevalent findings, 10.5% (810/7737) of positive cases had findings in the remaining 22 genes. Six FSGS-related genes (WT1, LMX1B, INF2, TRPC6, NPHS1, APOL1) were strongly associated with GD phenotypes (odds ratios 1.86 - 10.26; p < 0.016). Conclusion: Identification of causative variants spanning 26 genes in this cohort illustrates the genetic heterogeneity of FSGS. Notably, several of the FSGS-related genes with the highest prevalence of positive findings were not among those with the strongest associations with GD phenotype. This suggests that patients with these variants may have clinical presentations that are mild and/or precede GD. As FSGS is a histologic indication of later stage disease, longitudinal clinical information would provide insight into the prognosis of individuals with variants in these genes.