Background and objectives Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. Design, setting, participants, & measurements Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. Results In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. Conclusions Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.
|Number of pages||10|
|Journal||Clinical Journal of the American Society of Nephrology|
|Publication status||Published - 2018 Jan 6|
Bibliographical noteFunding Information:
F.H. is the William E. Harmon Professor of Pediatrics. This research was supported by grants from the National Institutes of Health to F.H. (DK076683) and J.K.W. (DK007726-31A1). The Yale Center for Mendelian Genomics is funded by U54 HG006504 granted to R.P.L. and by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program to J.B. K. Funding to W.T. through the American Society of Nephrology Benjamin J. Lipps Research Fellowship Award (FP01014311) and DK007726-31A1. H.Y.G. was supported by the Basic Science Research Program through the National Research Foundation of Korea (2015R1D1A1A01056685). T.H. is supported by a Research Fellowship from the Deutsche Forschungsgemeinschaft (DFG) (HE 7456/1-1). T.J.-S. is supported by the DFG (Jo 1324/1-1). A.J.M. is supported by National Institutes of Health T32-AR053461-04 Postdoctoral Fellow Training Grant. M.N. is supported by the Ii-numa-Tsuchiya Foundation for Overseas Research. F.O. is supported by the European Community’s Seventh Framework Programme (FP7/2007-2013) (European Consortium for High-Throughput Research in Rare Kidney Diseases, grant 2012-305608). The Nephrogenetics Laboratory at Hacettepe University was established by the Hacettepe University Infrastructure Project (grant 06A101008). A.V. is supported by the Manton Center for Orphan Diseases Research grant. A.T.v.d.V. is supported by the Postdoctoral Research Fellowship (VE 916/1-1) from the DFG. E.W. is supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07).
All Science Journal Classification (ASJC) codes
- Critical Care and Intensive Care Medicine