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

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.

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.

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.

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.