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

Abstract

Hereditary diseases; Nephrotic syndrome; Steroid-resistant

Enfermedades hereditarias; Síndrome nefrótico; Resistente a los esteroides

Malalties hereditàries; Síndrome nefròtica; Resistent als esteroides

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.

This work was supported by grants from the Fundación Íñigo Álvarez de Toledo, the Instituto de Salud Carlos III (PI18/00 378 under FIS/FEDER and RD21/0005/0020-RICORS funds to M.A.G.-G.; RD21/10 005/0001-RICORS to G.F.-J.) and the Xunta de Galicia (IN607B-2016/020 to M.A.G.-G., funded by the European Union “NextGenerationEU” Facility for recovery and resilience). None of the funders had any role in study design, data collection, analysis, reporting or the decision to submit for publication.