BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.