Genetic mutation patterns in Indonesian children with primary steroid-resistant nephrotic syndrome

Approximately 10-30% of pediatric cases of steroid-resistant nephrotic syndrome (SRNS) have pathogenic monogenic variants, particularly in primary SRNS. Identifying these variants aids in predicting outcomes, guiding treatment, and enabling genetic counseling. In Indonesia, data on genetic mutation patterns in pediatric SRNS are still limited.

A cross-sectional study was conducted using whole-exome sequencing (WES) to detect variants of genetic origin in children diagnosed with primary SRNS at Indonesia's National Referral Hospital, Cipto Mangunkusumo. We assessed the relationship between genetic findings and clinical features, including age at onset, treatment response, kidney biopsy, and kidney function.

Among 60 children with primary SRNS, 9 subjects (15%) harbored pathogenic or likely pathogenic variants across 8 genes (CUBN, AVIL, TRPC6, INF2, COL4A4, LAMA5, INVS, and FGA). Variants included stop-gained (n = 4), missense (n = 4), splice site (n = 1), and frameshift (n = 1), with both autosomal recessive and dominant inheritance observed. Two subjects had compound heterozygous variants. Most variant-positive subjects were male (6/9), had disease onset before age 3, and showed diverse histology (FSGS, MCD, or mesangial/membranoproliferative lesions). Four showed extrakidney features: peripheral neuropathy, high myopia, microcephaly with short stature, and hearing loss. While 53.3% responded to cyclosporin, over half remained in non-remission.

This study reveals the genetic and phenotypic heterogeneity of primary SRNS in Indonesian children. The identification of diverse pathogenic variants underscores the utility of WES, even in cases responsive to cyclosporin. Genetic testing should be integrated into routine SRNS evaluation, especially in atypical presentations or early-onset of the disease.