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

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Focal segmental glomerulosclerosis (FSGS) has recognized genetic causes, but patient selection for genetic studies remains unclear.
• Determining the frequency and distribution of genetic variants in specific FSGS subtypes is crucial for diagnosis and management.

Purpose of the Study:

• To investigate the prevalence and patterns of genetic variants in adult-onset steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and FSGS of undetermined cause (FSGS-UC).
• To assess the utility of genetic testing in routine clinical practice for these FSGS patient groups.

Main Methods:

• Targeted exome sequencing of 84 glomerulopathy-associated genes was performed on 76 patients with adult-onset SRNS-FSGS or FSGS-UC.
• Secondary causes of FSGS were excluded prior to genetic analysis.

Main Results:

• FSGS-related disease-causing variants were identified in 35.5% of patients.
• COL4A3-5 genes (29.3%) and NPHS2 mutations (16.2%) were the most common genetic findings.
• Genetic variants were found irrespective of age, proteinuria, kidney function, or family history, though hematuria was more prevalent in genetically affected patients.

Conclusions:

• Genetic variants are prevalent in a significant portion of patients with SRNS-FSGS and FSGS-UC.
• Genetic testing should be integrated into the routine clinical workup for diagnosing FSGS in these patient populations.