Analysis of the Coding Regions of 33,894 Individuals Identifies Known and Novel Gene Associations for Idiopathic Nephrotic Syndrome

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Background: Approximately 120 genes have been identified as associated with either a monogenic form of idiopathic nephrotic syndrome (INS) or a kidney disease that phenocopies focal segmental glomerulosclerosis (FSGS). Systematic rare variant studies across the age of onset, response to therapy, and ancestries are still lacking. Methods: We conducted an exome sequencing (ES) study on 5,259 cases with INS caused by FSGS or minimal change disease (MCD), and 28,635 population controls. A comprehensive clinical genomic screening was performed to identify “solved cases” harboring diagnostic/pathogenic Mendelian mutations in known FSGS genes. Per-gene burden of rare coding variants was assessed by exome-wide collapsing analysis comparing abovementioned cases and controls dominant and recessive models. Analyses were conducted on the entire dataset and then again after removal of solved cases and cases with APOL1 high-risk genotypes. Results: We identified rare pathogenic variants in 704 (13.39%) cases, with the most frequent diagnoses attributable to NPHS2, COL4A3, COL4A5, COL4A4, NPHS1, WT1, and INF2 variants, but with different distribution according to genetic ancestry (AFR having the lowest yield), age of onset (diagnostic rate doubles in pediatric than adults), and response to therapy (lower but non-zero yield in SSNS). Exome-wide collapsing analysis retrieved association for these known genes: WT1 (best P= 1.09 × 10-23), COL4A5 (best P= 2.37 × 10-17), INF2 (best P= 1.87 × 10-11), and others, under dominant models, and NPHS1 (best P= 1.56 × 10-21), NPHS2 (best P= 3.93 × 10-15), SMARCAL1 (best P= 9.91 x 10-9) and several others, under recessive models. Removal of solved cases and re-analysis prioritized 6 novel candidate genes: two exceeded the 5% false discovery rate based on 1,000 permutations (FAM71B and SAV1); four (RAPGEF2, RALBP1, GNB1L, HMOX1) when mutated in the mouse result in glomerulopathy. Conclusion: These findings expand our understanding of the genetic underpinning of INS, identify novel candidate genes, and highlight the high genetic heterogeneity of disease.

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