RT Journal Article SR Electronic T1 Simultaneous Sequencing of 24 Genes Associated with Steroid-Resistant Nephrotic Syndrome JF Clinical Journal of the American Society of Nephrology JO CLIN J AM SOC NEPHROL FD American Society of Nephrology SP 637 OP 648 DO 10.2215/CJN.07200712 VO 8 IS 4 A1 McCarthy, Hugh J. A1 Bierzynska, Agnieszka A1 Wherlock, Matt A1 Ognjanovic, Milos A1 Kerecuk, Larissa A1 Hegde, Shivaram A1 Feather, Sally A1 Gilbert, Rodney D. A1 Krischock, Leah A1 Jones, Caroline A1 Sinha, Manish D. A1 Webb, Nicholas J.A. A1 Christian, Martin A1 Williams, Margaret M. A1 Marks, Stephen A1 Koziell, Ania A1 Welsh, Gavin I. A1 Saleem, Moin A. A1 , YR 2013 UL http://cjasn.asnjournals.org/content/8/4/637.abstract AB Background and objectives Up to 95% of children presenting with steroid-resistant nephrotic syndrome in early life will have a pathogenic single-gene mutation in 1 of 24 genes currently associated with this disease. Others may be affected by polymorphic variants. There is currently no accepted diagnostic algorithm for clinical genetic testing. The hypothesis was that the increasing reliability of next generation sequencing allows comprehensive one-step genetic investigation of this group and similar patient groups.Design, setting, participants, & measurements This study used next generation sequencing to screen 446 genes, including the 24 genes known to be associated with hereditary steroid-resistant nephrotic syndrome. The first 36 pediatric patients collected through a national United Kingdom Renal Registry were chosen with comprehensive phenotypic detail. Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing.Results Analysis revealed known and novel disease-associated variations in expected genes such as NPHS1, NPHS2, and PLCe1 in 19% of patients. Phenotypically unexpected mutations were also detected in COQ2 and COL4A4 in two patients with isolated nephropathy and associated sensorineural deafness, respectively. The presence of an additional heterozygous polymorphism in WT1 in a patient with NPHS1 mutation was associated with earlier-onset disease, supporting modification of phenotype through genetic epistasis.Conclusions This study shows that next generation sequencing analysis of pediatric steroid-resistant nephrotic syndrome patients is accurate and revealing. This analysis should be considered part of the routine genetic workup of diseases such as childhood steroid-resistant nephrotic syndrome, where the chance of genetic mutation is high but requires sequencing of multiple genes.