Population Modeling Defines Adult-Onset FSGS Caused by NPHS2 Pathogenic Variants

Introduction A better understanding of disease burden is imperative to inform targeted therapies for monogenic focal segmental glomerulosclerosis (FSGS). Here, population modeling was used to estimate genotype frequencies in NPHS2 , the most common gene implicated in childhood FSGS. These were then compared with patient cohorts. Methods Over 1.2 million genomes from 5 international databases were included for population modeling. Pathogenic variants were assigned if in agreement with the ClinVAR database, according to American College of Medical Genetics and Genomics criteria, or based on predictions from 4 independent in silico algorithms. Modeled genotypes were compared with cohorts from Natera Renasight ( n = 92,984), a gene panel used for clinical renal genetic testing in the United States, and the DUPLEX study ( n = 355) (NCT03493685). Results Modeling confirmed high frequency of R138Q in Northwestern Europe associated with early-onset disease. Unexpectedly, a high proportion (77%) of the US cases were predicted R229Q compound heterozygosity, associated with adult-onset disease. Half of modeled R229Q genotypes occur in trans with A284V, prevalent among individuals with admixed American ancestry (previously Latin American). Of the 67 patients having pathogenic NPHS2 variants identified by Renasight, 58% were R229Q compound heterozygotes (37% [R229Q];[A284V]). Of the 15 patients having pathogenic NPHS2 variants in DUPLEX, 80% were R229Q compound heterozygotes (33% [R229Q];[A284V]). The Renasight and DUPLEX data confirm trends in modeled genotype frequencies. Conclusion Population modeling reveals a larger than expected R229Q mutational burden in the United States, largely explained by European R229Q in trans with the A284V variant which is prevalent in admixed American ancestry. This adult-onset subgroup is likely underdiagnosed, and critically emphasises genetic screening in adult FSGS, to stratify patients for immunosuppression avoidance, and targeted therapies for NPHS2 nephropathy.