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INTRODUCTION: The profile of genetic and nongenetic factors associated with progression to kidney failure (KF) in steroid-resistant nephrotic syndrome (SRNS) is largely unknown in admixed populations.METHODS: A total of 101 pediatric patients with primary SRNS were genetically assessed targeting Mendelian causes and status with a 62-NS-gene panel or whole exome sequencing, as well as genetic ancestry. Variant pathogenicity was evaluated using the American College Medical of Genetics and Genomics (ACMG) criteria.RESULTS: Focal segmental glomerulosclerosis (FSGS) was diagnosed in 54% of patients whereas familial disease was reported by 13%. The global genetic ancestry was 65% European, 22% African, 10.5% Native American, and 2% East-Asian, while 96% of cases presented with the first 3 components. high-risk genotypes were identified in 8% of families and causative Mendelian variants in 12%:  = 3,  = 3,  = 2,  = 2,  = 1, and  = 1. Two novel causative variants arose in the Native American background. The percentage of African genetic ancestry did not associate with the number of risk alleles. Forty-four percent of all patients progressed to KF. Mendelian forms and high-risk genotypes were associated with faster progression to KF. Cox regression analyses revealed that higher non-European genetic ancestry, self-declared non-White ethnicity, age of onset <1 year or â‰¥9 years, and non-minimal change disease (MCD) histology associated with higher risk of KF, independently of genetic findings.CONCLUSION: Mendelian variants and high-risk genotype compose a unique causative genetic profile associated with pediatric SRNS in this highly admixed population, accounting for approximately 20% of families. This ancestry pattern is consistent with the identification of high-risk genotypes in children with low proportion of African genetic ancestry. Self-declared ethnicity, age of manifestation and histology were independently associated with the risk of KF.