Genetic testing in focal segmental glomerulosclerosis: in whom and when?

Abstract

Background: Genetic causes are increasingly recognized in patients with focal segmental glomerulosclerosis (FSGS), but it remains unclear which patients should undergo genetic study. Our objective was to determine the frequency and distribution of genetic variants in steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and in FSGS of undetermined cause (FSGS-UC).

Methods: We performed targeted exome sequencing of 84 genes associated with glomerulopathy in patients with adult-onset SRNS-FSGS or FSGS-UC after ruling out secondary causes.

Results: Seventy-six patients met the study criteria; 24 presented with SRNS-FSGS and 52 with FSGS-UC. We detected FSGS-related disease-causing variants in 27/76 patients (35.5%). There were no differences between genetic and non-genetic causes in age, proteinuria, glomerular filtration rate, serum albumin, body mass index, hypertension, diabetes or family history. Hematuria was more prevalent among patients with genetic causes. We found 19 pathogenic variants in COL4A3-5 genes in 16 (29.3%) patients. NPHS2 mutations were identified in 6 (16.2%) patients. The remaining cases had variants affecting INF2, OCRL, ACTN4 genes or APOL1 high-risk alleles. FSGS-related genetic variants were more common in SRNS-FSGS than in FSGS-UC (41.7% vs 32.7%). Four SRNS-FSGS patients presented with NPHS2 disease-causing variants. COL4A variants were the most prevalent finding in FSGS-UC patients, with 12 patients carrying disease-causing variants in these genes.

Conclusions: FSGS-related variants were detected in a substantial number of patients with SRNS-FSGS or FSGS-UC, regardless of age of onset of disease or the patient's family history. In our experience, genetic testing should be performed in routine clinical practice for the diagnosis of this group of patients.

Keywords: FSGS; hereditary diseases; nephrotic syndrome; podocytopathy; steroid-resistant.

Figure 1:

Screening flowchart. Patient flow through the study. Screening population included all adult patients with biopsy-proven FSGS and SRNS or FSGS-UC. Reasons for screening failures were classified as follows: poor sample condition (n = 3), incomplete clinical information (n = 7), suspected secondary FSGS (n = 3), suspected primary FSGS (n = 15) and under 18 years old at the time of biopsy (n = 4).

Figure 2:

Diagnostic yield and genetic findings. Section (A) shows the diagnostic yield obtained. Section (B) summarizes the genetic findings, grouped by gene. One patient had a dual diagnosis (see Table 2).

Figure 3:

Genetic testing according to age (A) and glomerular filtration rate. (B) according to the inclusion criteria (whole cohort, FSGS-UC or SRNS-FSGS).

Figure 4:

Comparison of cohorts. This figure shows schematically our study and that of two other comparable cohorts; particularly, we show for each study the inclusion criteria considered, the NGS strategy employed, and the genetic results obtained. Section (A) refers to our cohort. The genetic results are represented both for the global cohort and broken down into the two considered subgroups: the FSGS-UC cohort and the SRNS-FSGS cohort. Section (B) shows the results of Gribouval et al. [8]. Section (C) shows the results of Gast et al. [9].