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Kidney Week

Abstract: FR-PO794

Variable Penetrance of the Therapy-Resistant Phenotype Among Children with the Genetic Form of Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Lai Yee, Jennifer, University of Michigan, Ann Arbor, Michigan, United States
  • Zee, Jarcy, Arbor Research Collaborative for Health, Ann Arbor, Michigan, United States
  • Fermin, Damian, University of Michigan, Ann Arbor, Michigan, United States
  • Mcnulty, Michelle, University of Michigan, Ann Arbor, Michigan, United States
  • Vega-Warner, V., University of Michigan, Ann Arbor, Michigan, United States
  • Sampson, Matt G., University of Michigan, Ann Arbor, Michigan, United States
Background

Currently, genetic forms of nephrotic can be classified as highly penetrant, pathogenic variants in single genes (“monogenic”) or common risk alleles contributing to the diseases pathogenesis such as APOL1 high-risk (HR) genotypes. Monogenic NS is thought to be therapy-resistant, with an inability to achieve complete remission (CR) and APOL1 NS has a lower odd of achieving CR. However, there have been reports that some patients with monogenic diseases may achieve CR. Factors associated with remission among genetic NS is still unclear. Therefore, this study used a large North American cohort of children with NS to (1) describe the prevalence of CR as a function of genetic profile and (2) identify factors potentially modifying the CR phenotype.

Methods

70 genes implicated in monogenic forms of NS and the two APOL1 risk alleles were analyzed in 215 children from the Nephrotic Syndrome Study Network (NEPTUNE) who had undergone whole genome sequencing. A variant pathogenicity pipeline was applied to identify patients with putative monogenic NS and APOL1 HR genotypes. General characteristics and CR were compared among patients classified with putative monogenic NS, APOL1-attributed NS, and no know genetic form of NS.

Results

Monogenic NS was found in 15 patients (7%) and APOL1 attributed NS was found in 28 patients (13%). Compared to no known genetic NS, monogenic and APOL1 attributed NS had lower rate of ever achieving CR (83% vs 43% and 59%, p=0.002 and 0.01, respectively) and lower likelihood to achieve remission (Hazard ratio 0.4 for both, p = 0.02 and 0.009, respectively, at 6 months of follow up). Loss of function Mendelian variants and those co-existing with other Mendelian variants or APOL1 HR genotype, tended to result in lack of CR.

Conclusion

Children with monogenic or APOL1 attributed NS were significantly less likely to achieve CR. Despite this, a substantial proportion of children with genetic forms of NS still achieved CR. Mendelian variants and APOL1 HR alleles in this North American, population-based NS cohort appear to increase risk of not achieving CR, rather than being fully penetrant for this phenotype. Further functional analysis is essential in increasing the accuracy of classifying patients with monogenic NS and making subsequent clinical correlations.

Funding

  • Other NIH Support