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 nephro...
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Published in | Clinical kidney journal Vol. 16; no. 11; pp. 2011 - 2022 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Oxford University Press
01.11.2023
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
Lay Summary
Prevalence of genetic causes in patients with a histological diagnosis of focal segmental glomerulosclerosis (FSGS) is probably underestimated due to the diagnostic challenges in its diagnosis. The criteria for genetic testing in adult patients with FSGS remains unclear. In this study, we found that there is a high prevalence of genetic forms in FSGS with steroid-resistant nephrotic syndrome (41.7%) and FSGS of undetermined cause (32.7%). The most common genetic variants in adult-onset FSGS steroid-resistant nephrotic syndrome were NPHS2 gene mutations, whereas in FSGS of undetermined cause the most frequent genetic mutations were in COL4A genes. The age of onset of disease and the presence of a positive family history did not discriminate between genetic and non-genetic forms of FSGS. In conclusion, genetic testing should be performed in patients with FSGS and steroid-resistant nephrotic syndrome or FSGS of undetermined cause, regardless of the age of onset or family history of kidney disease. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 A.M.T. and N.C. contributed equally to this work. |
ISSN: | 2048-8505 2048-8513 |
DOI: | 10.1093/ckj/sfad193 |