Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity

Abstract

Genetic diagnosis of steroid-resistant nephrotic syndrome (SRNS) using Sanger sequencing is complicated by the high genetic heterogeneity and phenotypic variability of this disease. We aimed to improve the genetic diagnosis of SRNS by simultaneously sequencing 26 glomerular genes using massive parallel sequencing and to study whether mutations in multiple genes increase disease severity. High-throughput mutation analysis was performed in 50 SRNS and/or focal segmental glomerulosclerosis (FSGS) patients, a validation cohort of 25 patients with known pathogenic mutations, and a discovery cohort of 25 uncharacterized patients with probable genetic etiology. In the validation cohort, we identified the 42 previously known pathogenic mutations across NPHS1, NPHS2, WT1, TRPC6, and INF2 genes. In the discovery cohort, disease-causing mutations in SRNS/FSGS genes were found in nine patients. We detected three patients with mutations in an SRNS/FSGS gene and COL4A3. Two of them were familial cases and presented a more severe phenotype than family members with mutation in only one gene. In conclusion, our results show that massive parallel sequencing is feasible and robust for genetic diagnosis of SRNS/FSGS. Our results indicate that patients carrying mutations in an SRNS/FSGS gene and also in COL4A3 gene have increased disease severity.

Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome

“…1 Most children with idiopathic NS respond well to steroids, but 10%-20% of affected children are categorized as having steroid-resistant NS (SRNS). [2][3][4][5][6] SRNS is a clinically and genetically heterogeneous renal disorder that might have an immunological, structural, or functional etiology. 2,5,[7][8][9] Higher rates of genetic delineation are expected in earlyonset SRNS.…”

Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life

“…This allows the subsequent bioinformatics in silico analysis of only the genes of interest in a candidate gene approach or the analysis of any other gene of the total 22,000 in the human genome. The same approach provides the information that may prove useful in identifying genes not previously suspected [39,49,50,51] or resolving conditions of digenic/oligogenic inheritance [52,53] or identifying modifier genes. Studying a well-characterized cohort of patients is mandatory for reaching reliable and useful conclusions.…”

Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort

“…1 Published reports suggest that monogenic causes are responsible for a substantial portion of NS, and these patients are resistant to immunosuppressive treatment. [2][3][4][5][6] These prevalence estimates and clinical correlates can influence decisions to screen patients for monogenic NS as well as the subsequent management. Given this and the increasing availability of sequencing technology, there is growing interest in expanding the use of genetic screening to diagnose monogenic NS.…”