1. Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome
- Author
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Heon Yung Gee, Richard P. Lifton, Aytül Noyan, Stefan Kohl, Weizhen Tan, Michael A. J. Ferguson, Neveen A. Soliman, Deborah R. Stein, Jing Chen, Svjetlana Lovric, J. Magdalena Schmidt, Jameela A. Kari, Avram Z. Traum, Jia Rao, Gil Chernin, Sherif El Desoky, Radovan Bogdanovic, Nadine Benador, Werner L. Pabst, Hanan M. Fathy, Jeffrey B. Kopp, Jillian K. Warejko, Asaf Vivante, Henry Fehrenbach, Detlef Bockenhauer, Carolin E. Sadowski, Velibor Tasic, Robert B. Ettenger, Amelie T. van der Ven, Shrikant Mane, Ankana Daga, Jeffrey Hopcian, Martin Zenker, Markus J. Kemper, Amar J. Majmundar, Erkin Serdaroglu, Ronen Schneider, Fatih Ozaltin, Ghaleb Daouk, Natasa Stajic, Nancy Rodig, Jennifer A. Lawson, Reyner Loza Munarriz, Melissa A. Cadnapaphornchai, Hadas Ityel, Shazia Ashraf, Rainer Büscher, Dominik N. Müller, Makiko Nakayama, Michelle A. Baum, Seema Hashmi, Ludmila Podracka, David Schapiro, Daniela A. Braun, Shirlee Shril, Michael J. Somers, Eugen Widmeier, Tilman Jobst-Schwan, Friedhelm Hildebrandt, Sevcan A. Bakkaloglu, and Tobias Hermle
- Subjects
Adult ,Genetic Markers ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Candidate gene ,Heredity ,Nephrotic Syndrome ,Adolescent ,Epidemiology ,DNA Mutational Analysis ,Medizin ,030232 urology & nephrology ,Critical Care and Intensive Care Medicine ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Mutation Rate ,Predictive Value of Tests ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Child ,Exome ,Congenital nephrotic syndrome ,Genetic Association Studies ,Exome sequencing ,Phenocopy ,Transplantation ,business.industry ,Infant ,Original Articles ,Prognosis ,medicine.disease ,Pedigree ,Steroid-resistant nephrotic syndrome ,Phenotype ,030104 developmental biology ,Nephrology ,Child, Preschool ,Mutation ,Female ,Age of onset ,business ,Nephrotic syndrome - Abstract
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 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.
- Published
- 2017