Contribution of Recessive Ciliopathy Genes in a Highly Consanguineous Adult Cohort with Biopsy-Proven Focal Segmental Glomerulosclerosis

Abstract Background Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome in adults and frequently progresses to end-stage renal disease. Emerging evidence suggests recessive ciliopathy genes contribute to glomerular disease, particularly in consanguineous populations, but their role in adult biopsy-proven FSGS remains incompletely defined. This study aimed to determine the frequency and clinical impact of pathogenic variants in recessive ciliopathy genes among adults with FSGS from a highly consanguineous Middle Eastern population. Methods We conducted a case-control study including 35 adults with biopsy-proven FSGS and 20 unaffected individuals with normal kidney function from Sulaymaniyah, Iraq. All participants underwent targeted next-generation sequencing of a 98-gene panel on the Ion S5 platform. Variants were classified according to 2015 American College of Medical Genetics and Genomics (ACMG) criteria; only pathogenic (P) and likely pathogenic (LP) variants in recessive ciliopathy genes were analyzed. Formal rare-variant burden analysis was performed. Demographic and clinical data were compared between groups. Results Biallelic ciliopathy variants were identified in 16 of 35 FSGS patients (45.7%) versus 0 of 20 controls (p < 0.001; OR 34.7, 95% CI 1.9-618.7). Seven ciliopathy genes were implicated: INPP5E (10 patients, 28.6%), BBS2 (7 patients, 20.0%), CPLANE1 (6 patients, 17.1%), CEP290 (4 patients, 11.4%), TCTN2 (1 patient), BBS7 (1 patient), and NPHP3 (1 patient). All identified variants were absent or ultra-rare (allele frequency < 0.000007) in gnomAD v4.1, confirming their rarity. Ciliopathy-positive patients demonstrated universal proteinuria, higher rates of hematuria (81.3% vs 21.1%, p < 0.001), more severe renal dysfunction (serum creatinine 3.6 ± 0.9 vs 1.2 ± 0.4 mg/dL, p < 0.001), and increased hypertension prevalence (68.8% vs 31.6%, p = 0.002) compared with ciliopathy-negative FSGS patients. Conclusions In this highly consanguineous Middle Eastern cohort, recessive ciliopathy gene variants, particularly in INPP5E, BBS2, and CPLANE1, were frequent among adults with biopsy-proven FSGS and associated with severe progressive kidney disease. These findings support incorporating ciliopathy gene testing into the diagnostic evaluation of adults with FSGS from consanguineous families or with positive family history of kidney disease.