Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

Autor:	Bierzynska A; Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK., McCarthy HJ; Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK., Soderquest K; Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK., Sen ES; Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK., Colby E; Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK., Ding WY; Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK., Nabhan MM; Egyptian group for orphan renal diseases (EGORD), Department of paediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt., Kerecuk L; Birmingham Children's Hospital, Birmingham, UK., Hegde S; University Hospital of Wales, Cardiff, UK., Hughes D; Royal Hospital for Children, Glasgow, UK., Marks S; Great Ormond Street Hospital, London, UK., Feather S; St James's University Hospital, Leeds, UK., Jones C; Alder Hey Children's Hospital, Liverpool, UK., Webb NJ; Department of Paediatric Nephrology and NIHR/Wellcome Trust Clinical Research Facility, University of Manchester, Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Manchester, UK., Ognjanovic M; Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK., Christian M; Nottingham Children's Hospital at the QMC, UK., Gilbert RD; Southampton Children's Hospital and University of Southampton School of Medicine, Southampton, UK., Sinha MD; Guy's and St. Thomas' Hospital, London, UK., Lord GM; Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK., Simpson M; Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, UK., Koziell AB; Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK., Welsh GI; Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK., Saleem MA; Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK. Electronic address: M.Saleem@bristol.ac.uk.
Jazyk:	angličtina
Zdroj:	Kidney international [Kidney Int] 2017 Apr; Vol. 91 (4), pp. 937-947. Date of Electronic Publication: 2017 Jan 20.
DOI:	10.1016/j.kint.2016.10.013
Abstrakt:	Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management. (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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