title: Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.
abstract: 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.
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bierzynska
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: McCarthy
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: Soderquest
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Sen
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Colby
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK.
authors.forename: Wen Y
authors.initials: WY
authors.lastname: Ding
authors.affiliation: Egyptian group for orphan renal diseases (EGORD), Department of paediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Marwa M
authors.initials: MM
authors.lastname: Nabhan
authors.affiliation: Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Larissa
authors.initials: L
authors.lastname: Kerecuk
authors.affiliation: University Hospital of Wales, Cardiff, UK.
authors.forename: Shivram
authors.initials: S
authors.lastname: Hegde
authors.affiliation: Royal Hospital for Children, Glasgow, UK.
authors.forename: David
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Great Ormond Street Hospital, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Marks
authors.affiliation: St James's University Hospital, Leeds, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Feather
authors.affiliation: Alder Hey Children's Hospital, Liverpool, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Nicholas J A
authors.initials: NJ
authors.lastname: Webb
authors.affiliation: Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.
authors.forename: Milos
authors.initials: M
authors.lastname: Ognjanovic
authors.affiliation: Nottingham Children's Hospital at the QMC, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Christian
authors.affiliation: Southampton Children's Hospital and University of Southampton School of Medicine, Southampton, UK.
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Gilbert
authors.affiliation: Guy's and St. Thomas' Hospital, London, UK.
authors.forename: Manish D
authors.initials: MD
authors.lastname: Sinha
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
authors.affiliation: Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Simpson
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Ania B
authors.initials: AB
authors.lastname: Koziell
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, UK. Electronic address: M.Saleem@bristol.ac.uk.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods*; D040941:Heredity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D010375:Pedigree; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries; D012307:Risk Factors; D006113:United Kingdom; D025721:WT1 Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D025721:WT1 Proteins; C583751:WT1 protein, human; C113267:nephrin
keywords: cytoskeleton; focal segmental glomerulosclerosis; nephrotic syndrome; pediatric nephrology; podocyte; proteinuria