A Novel CRB2 Mutation Associated With FSGS and ESRD in an Adult Patient

Background Chronic kidney disease (CKD) is a major global health concern, with a substantial proportion of cases that remain of undetermined cause. Mutations in genes affecting podocyte structure and function, are increasingly recognized as causes of focal segmental glomerulosclerosis (FSGS), a common but highly nonspecific histological pattern of kidney injury, that ultimately lead to CKD. Case Presentation We report the case of a 55‐year‐old male who presented with hypertension and end‐stage renal disease (ESRD) of unknown etiology. He had a progressive decline in kidney function and proteinuria beginning in young adulthood. A kidney biopsy showed a pattern of FSGS. A comprehensive workup did not identify autoimmune or inflammatory causes. Whole‐exome sequencing detected a previously undescribed heterozygous CRB2 mutation (c.1037G > T, p.Cys346Phe), predicted to be deleterious. Discussion Animal models of CRB2 deprivation in podocytes showed progression toward FSGS. In humans, CRB2 mutations have previously been linked to severe early‐onset nephrotic syndrome, typically in homozygous or compound heterozygous states. This is the first report of an adult‐onset CRB2‐associated FSGS in a heterozygous state, suggesting a milder disease course with a progressive kidney decline. As with other genetic forms of FSGS, we hypothesize that heterozygous CRB2 mutations may permit near‐normal renal function for years until cumulative stressors trigger podocyte injury and CKD progression. Conclusion This case expands the clinical spectrum of CRB2‐related kidney disease and highlights the importance of genetic testing in adults with unexplained CKD. Identifying genetic forms of CKD may refine diagnostic and therapeutic approaches in nephrology.