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

Abstract

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.

Keywords: APOL1; children; focal segmental glomerulosclerosis; genetic ancestry; monogenic chronic kidney disease; steroid-resistant nephrotic syndrome.

Graphical abstract

Figure 1

(a) Genes included in the nephrotic syndrome (NS) panel. (b) Demographic, clinical, laboratory, and histological characterization of the patient population. (c) Distribution of Mendelian and APOL1 high-risk genotype-related pediatric forms of NS among the evaluated Brazilian steroid-resistant nephrotic syndrome (SRNS) or congenital nephrotic syndrome (CNS)/focal segmental glomerulosclerosis (FSGS) families. CG, collapsing glomerulopathy; FSGS, focal and segmental glomerulosclerosis; GN, glomerulonephritis; KF, kidney failure; MCD, minimal change disease.

Figure 2

(a) Renal survival was lower in patients who self-declared being non-White, and (b) when genetic ancestry was addressed, patients with higher percentages of non-European ancestry reached kidney failure faster than patients with higher percentages of European ancestry. Renal survival after NS onset was lower in patients (c) with Mendelian causes, (d) APOL1 high-risk genotypes, (e) NS onset before 1 year or at or after 9 years of age. (f) Cox regression multivariable analysis revealed that age of NS onset before 1 year or at or after 9 years of age increase the risk to reach kidney failure. NS, nephrotic syndrome.

Figure 3

(a) Conservation of COQ2 p.Pro142 and p.Phe383. (b) Structure of p-hydroxibenzoato profenil transferase. COQ2 p.Pro142 and p.Phe383 are close to the active site, possibly changing its volume and, consequently, its transprenylation activity (mutated residues colored in red). (c) Surface volume of the wild type model in blue, p.Pro142 in red, and p.Phe383 in green.