Pathogenic variants in COL4A3, COL4A4, JAG1, and NPHS2 genes in focal segmental glomerulosclerosis: Insights from...

Monogenic causes of focal segmental glomerulosclerosis (FSGS) are increasingly recognized, but data from highly consanguineous Middle Eastern populations remain limited. This study explored the diagnostic yield and descriptive genotype-phenotype correlations of a targeted gene panel in Iraqi patients with biopsy-proven FSGS from a cohort enriched for familial, early-onset, and consanguineous disease.

Thirty consecutive patients with histologically confirmed FSGS underwent next-generation sequencing using a 98-gene renal disease panel. Variants were classified according to ACMG guidelines and interpreted with clinical and histopathological findings. Exploratory analyses compared variant-positive and variant-negative patients and assessed simple clinical predictors of a positive genetic result.

Pathogenic variants were identified in 10 of 30 patients (33.3%) in COL4A3 (n = 2), COL4A4 (n = 3), JAG1 (n = 3), and NPHS2 (n = 2). Two novel frameshift variants were detected in COL4A4 (c.3109_3110delCT) and JAG1 (c.1713delC). Variant-positive patients had earlier disease onset than variant-negative patients (20.6 ± 7.2 vs. 30.1 ± 11.6 years; p = 0.022). In this small, enriched cohort, a simple triage rule based on age of onset <25 years, extrarenal manifestations, or family history showed 100% sensitivity and negative predictive value, but requires external validation before clinical use. Gene-group analyses suggested collagen IV-related disease, recessive podocytopathy, and Alagille-spectrum disease in relevant subgroups.

In this predominantly familial and early-onset FSGS cohort, one-third of patients harbored pathogenic variants, supporting the value of gene-panel testing in selected young or syndromic patients while underscoring the need for validation in larger, more representative cohorts.