Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression

Abstract

In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid-resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner.

Keywords: genetic variant; high-throughput DNA sequencing; immunosuppression; proteinuria.

Figure 1.

Flow diagram showing mechanisms for filtering variants to identify the variants of potential pathogenicity. AA, amino acid; HGMD, Human Gene Mutation Database; ins/del, insertion/deletion; MAF, minor allele frequency; NHLBI, National Heart, Lung, and Blood Institute; snp, single nucleotide polymorphism.

Figure 2.

Analysis of patients’ genotypes in relation to age at onset of nephrotic syndrome and response to treatments. (A) Percentage of mutations in patients with SRNS or SSNS. Patients with mutated SRNS are represented in white, and patients with not mutated SRNS are represented in gray. Patients with SSNS are represented in the striped column. (B) Age at onset in patients affected by nephrotic syndrome. Patients with SRNS are classified as mutated (white box) or not mutated (gray box); Patients with SSNS are represented in the striped box. In each box, the bottom and top of the box are always the first and third quartiles, and the band inside the box is always the second quartile (the median). Squares inside each box represent the mean value for each group. The whiskers indicate variability outside the upper and lower quartiles, with the end of the whiskers representing fifth and 95th percentiles. Triangles represent first and 99th percentiles in each box. (C) Percentage of FSGS, minimal change disease (MCD), and diffuse mesangial sclerosis (DMS) pathologic findings in patients with mutated SRNS (white column) versus not mutated SRNS (gray column). (D) Percentage of responders to immunosuppressive treatment (IS) in patients with mutated SRNS (white column), not mutated SRNS (gray column), and SSNS (striped column). *P<0.05; **P<0.001.