A pediatric-onset case of chronic kidney disease caused by a novel sporadic ACTN4 variant and literature review.

Abstract

Background: The α-actinin-4 (ACTN4) gene encodes an actin-binding protein, which plays a crucial role in maintaining the structure and function of podocytes. Previous studies have confirmed that ACTN4 mutations can lead to focal segmental glomerulosclerosis-1 (FSGS1), a rare disease primarily manifesting in adolescence or adulthood, characterized by mild to moderate proteinuria, with some cases progressing slowly to end-stage renal disease.

Case presentation: We report a 12.5-year-old boy who presented with non-nephrotic range proteinuria, hyperuricemia, markedly reduced bilateral kidney volume, and stage 3 chronic kidney disease (CKD). An ophthalmic examination revealed optic disc dysplasia in the right eye. The results of whole-exome sequencing revealed a de novo variant in the ACTN4, a previously unreported variant.

Conclusions: We reported a novel sporadic ACTN4 variant and reviewed previously reported cases. Through analysis of the genotypes and clinical phenotypes of reported cases, we found that ACTN4 variants may not always present as FSGS1, and there was significant phenotypic heterogeneity among individuals. Notably, mutations affecting residues 260-265 are associated with collapsing glomerulopathy and rapid progression to end-stage kidney disease in prior studies, whereas the p.Ala278del variant in our case, located outside this region, exhibited stable CKD3. This suggests domain-specific genotype-phenotype correlations. However, this association requires further validation through additional cases and experiments. Our findings may have significant implications for clinical diagnosis, prognosis assessment, and scientific research on kidney diseases related to ACTN4 variants.