Steroid-Resistant Nephrotic Syndrome Is Associated With a Unique Genetic Profile in a Highly Admixed Pediatric Population

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Watanabe, Andreia ; Neves, Precil Diego Miranda de Menezes ; Nunes, Kelly ; Lerario, Antonio Marcondes ; Watanabe, Elieser Hitoshi ; Ferreira, Frederico Moraes ; Malheiros, Denise Maria Avancini Costa ; Narcizo, Amanda de Moraes ; Guaragna, Mara Sanches ; Araujo, Stanley de Almeida ; Cruz, Thais Medeiros ; Fontes, Jussara Soares ; Belangero, Vera Maria Santoro ; Vaisbich, Maria Helena ; Hildebrandt, Friedhelm ; Sampson, Matthew Gordon ; Onuchic, Luiz Fernando

• Tipo de documento: Artigo Científico
• Fonte: KIDNEY INTERNATIONAL REPORTS; v. 9, n. 12, p. 16-pg., 2024-12-03.

Resumo

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 APOL1 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. APOL1 high-risk genotypes were identified in 8% of families and causative Mendelian variants in 12%: NPHS1 = 3, NPHS2 = 3, PLCE1 = 2, WT1 = 2, COQ2 = 1, and CUBN = 1. Two novel causative variants arose in the Native American background. The percentage of African genetic ancestry did not associate with the number of APOL1 risk alleles. Forty-four percent of all patients progressed to KF. Mendelian forms and APOL1 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 >= 9 years, and non-minimal change disease (MCD) histology associated with higher risk of KF, independently of genetic findings. Conclusion: Mendelian variants and APOL1 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 APOL1 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. (c) 2024 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). (AU)

• Processo FAPESP: 20/02988-7 - Decodificando o impacto do microambiente e das vias de sinalização na saúde e na doença no cérebro, glândula adrenal e rim
• Beneficiário: Suely Kazue Nagahashi Marie
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Temático