Targeted NGS panel reveals a high burden of collagen IV, podocyte, and transcription factor gene mutations in biopsy-proven focal segmental glomerulosclerosis

Background The genetic architecture of focal segmental glomerulosclerosis (FSGS), a primary cause of nephrotic syndrome and progressive kidney failure, is still poorly understood among Middle Eastern populations. Monogenic and oligogenic forms of hereditary kidney disease are expected to be common in these populations. This study investigated genotype-phenotype associations and characterize the burden and spectrum of pathogenic and likely pathogenic variants in Iraqi individuals with biopsy-proven FSGS. Methods Twenty ethnically matched healthy controls and 35 patients with biopsy-confirmed FSGS were enrolled. A tailored next-generation sequencing panel spanning 98 genes linked to FSGS-glomerular and kidney disorders was used to evaluate genomic DNA. Variants were categorized in accordance with the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria after being filtered by population frequency. Downstream analyses comprised only pathogenic and likely pathogenic (LP/P) variants. Results In the FSGS cohort, LP/P variants were detected in 35 of the 98 genes, while no such variants were found in the controls. The predominant genetic pathway in this group was represented by the collagen type IV genes (COL4A3, COL4A4, and COL4A5), which were impacted in 31 patients (88.6%). 28 patients (80.0%) had mutations in podocyte-associated genes and 24 patients (68.6%) had mutations in transcription factor genes. Particularly in collagen IV, TRPC6, and JAG1, recurrent and truncating variants were commonly found. Hematuria, consanguinity, positive family history, and the development of end-stage renal disease were all strongly linked to LP/P variants in the collagen IV. Conclusions Targeted NGS panel analysis shows that Iraqi patients with FSGS confirmed by biopsy have a notably high occurrence of harmful mutations affecting collagen IV, podocyte proteins, and transcription factors. These findings demonstrate that both monogenic and oligogenic mechanisms play a major role in this highly consanguineous population and support the routine use of comprehensive renal gene panels for diagnosis, risk stratification, and family counseling in FSGS.