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Report for Clinical Trial NCT03326037

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Study of The Association of Mutations in The NPHS2 Gene and Nephrotic Syndrome in Children and Adults in Middle East

Nephrotic syndrome (NS) represents one of the most common diagnoses in pediatric and adult nephrology, with a prevalence of 16 per 100,000 children and 3 per 100,000 adults in Western countries. In most cases, the pathogenesis of NS remains elusive, and the clinical phenotype of patients does not allow discrimination among different causes. Thus, children with NS are usually treated with corticosteroids before a biopsy is taken, and approximately 80% of them respond to such a treatment. According to this observation, pediatric NS has been separated into two broad categories; Steroid-Sensitive Nephrotic Syndrome (SSNS) and Steroid-Resistant Nephrotic Syndrome (SRNS). In both these categories the biopsy result is usually Minimal Change Disease (MCD) while a few may show Focal and Segmental Glomerulosclerosis (FSGS). Although children affected by SSNS have good long-term prognosis, most patients with SRNS progress to End Stage Renal Disease (ESRD) within 2-10 years of diagnosis . In adults a biopsy diagnosis of FSGS is more common than in children and more patients will not respond to corticosteroids alone and will need additional immunosuppressant medication. About 40% will progress to ESRD within 10 years . Currently, at least 19 genes have been clearly identified with association to SRNS harboring ~300 independent mutations, conferring a considerable genetic heterogeneity to the disorder. Genetic testing is emerging as a useful diagnostic tool in SRNS as it has implications for clinical course, treatment response, risk for posttransplant proteinuria and prenatal diagnosis. An approach for genetic testing based on the current evidence seems cost-effective and may help in the best possible management of SRNS . The NPHS2 gene, is located on chromosome 1 and is also known as the Podocin gene. It encodes the podocin protein. Podocin is a 383-amino acid lipid-raft-associated protein localized at the slit diaphragm, where it is required for the structural organization and regulation of the glomerular filtration barrier. Its interaction with other slit diaphragm proteins eg. nephrin, NEPH1, CD2AP and TRPC6 is important in mechanosensation signaling, podocyte survival, cell polarity, and cytoskeletal organization . . It has been reported that variants in the NPHS2 gene are associated with NS . The commonly studied rs61747728 NPHS2 gene polymorphism also known as p.R229Q has been reported to be associated with NS and SRNS . However others have failed to report an association , which might be due to population differences. The rs61747728 is a non-synonymous variant found on exon 5 which is suggested to be involved in in altering the functional properties of podocin in vitro and possibly in vivo . The investigators will therefore investigate the frequency of the p.R229Q variant in Middle East patients with NS. Genetic analysis will have important implications in several aspects:- 1. Understanding the biology of the disease in this part of the world. 2. Counselling patients about their clinical course and what medication they will respond to. 3. Counselling patients about the possibility of a kidney transplant sooner in their disease course

NCT03326037 Nephrotic Syndrome
MeSH: Nephrotic Syndrome Nephrosis Syndrome
HPO: Nephrotic syndrome

1 Interventions

Name: Genotyping of the NPHS2 variant rs61747728

Description: Genotyping of the NPHS2 variant rs61747728 will be performed by Real-time TaqMan Allelic Discrimination Assay (Life technologies, CA, USA) according to standard manufacturer protocols. Allelic discrimination analysis will be performed and analyzed using ABI 7500 Fast Real-time PCR system SDS software (Life technologies, CA, USA)

Type: Genetic


Primary Outcomes

Description: participants will be monitored for up to 2 years and classified as steroid -sensitive nephrotic syndrome or steroid - resistant nephrotic syndrome according to clinical response to steroid therapy ( 1 mg prednisolone /kg) for total 6 weeks. Renal biopsy will be done for all patients above 5 years of age (MCD and FSGS) were included. Blood sample or buccal swab will be collected from all patients and genotyping of the NPHS2 gene variant will be performed to report number of participants with NPHS2 gene mutations to share our results with the treating clinicians so that counselling of the patients can be done in terms of advising for kidney transplant sooner in their clinical course, prognosis and family screening.

Measure: Number of participants achieving NPHS2 gene mutations (frequency of p.R229Q polymorphic site) in patients with steroid-resistant nephrotic syndrome in comparison with steroid - sensitive nephrotic syndrome

Time: Baseline to 2 years

Time Perspective: Prospective

Cohort


There is one SNP

SNPs


1 rs61747728

The commonly studied rs61747728 NPHS2 gene polymorphism also known as p.R229Q has been reported to be associated with NS and SRNS .

The rs61747728 is a non-synonymous variant found on exon 5 which is suggested to be involved in in altering the functional properties of podocin in vitro and possibly in vivo .

Genotyping : Genotyping of the NPHS2 variant rs61747728 will be performed by Real-time TaqMan Allelic Discrimination Assay (Life technologies, CA, USA) according to standard manufacturer protocols.



HPO Nodes


HPO:
Nephrotic syndrome
Genes 159
WDR73 BBS9 VAMP7 NUP107 INF2 TP53RK WDPCP SGPL1 WDR4 SOX9 RAG1 NUP160 LMNB2 SNAP29 TRNH LIG4 B2M NUP133 CASP10 COQ2 NUP107 GATA4 LAGE3 NLRP3 NUP107 BBS10 ND4 PLCE1 LYZ C8ORF37 FOXP3 TRNL1 BBS1 COL4A3 CEP290 WT1 ARHGDIA CRB2 COQ2 ANLN LAGE3 SRY C1R NUP85 BBS7 TRNQ TPRKB DCLRE1C NR5A1 STAT4 OSGEP MEFV TRNS2 IL7R TRPC6 SCARB2 COL4A5 FN1 PMM2 NPHS1 GATA3 FN1 C1QBP MAP3K1 MARS1 TTC8 WDR73 SPP1 TRNS1 WT1 PMM2 NPHP1 BBIP1 TPRKB TBC1D8B C3 LAMB2 TBX18 SMARCAL1 PAX2 SLC35A2 WDR4 NPHS1 LZTFL1 COL4A4 NUP133 TP53RK MYO1E IFIH1 ZFPM2 COX1 ARL6 WT1 SAA1 TRNF MAGI2 ND1 LMX1B BBS2 MKKS SERPINA1 IFT27 KANK2 OSGEP BBS5 SMARCAL1 CHD7 LMX1B TRNW COX3 TRIM32 LAMB2 NUP93 PDSS2 NPHS2 SDCCAG8 MKS1 WT1 NR0B1 C1QA WT1 COL4A3 MEFV ZNF592 ITGA3 DGKE COX2 DMRT3 APOA1 PTPRO SLC17A5 NUP133 WDR73 RAG2 IRAK1 PRKCD GSN WT1 ZAP70 EMP2 IL2RG CCND1 PDSS2 ND6 BBS4 GLA ADA NUP205 CHST14 COQ8B ND5 ZAP70 RMRP FGA BBS12 MME IFT172 COQ6 WWOX