Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.
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.
['Bierzynska|Agnieszka|A|', 'McCarthy|Hugh J|HJ|', 'Soderquest|Katrina|K|', 'Sen|Ethan S|ES|', 'Colby|Elizabeth|E|', 'Ding|Wen Y|WY|', 'Nabhan|Marwa M|MM|', 'Kerecuk|Larissa|L|', 'Hegde|Shivram|S|', 'Hughes|David|D|', 'Marks|Stephen|S|', 'Feather|Sally|S|', 'Jones|Caroline|C|', 'Webb|Nicholas J A|NJ|', 'Ognjanovic|Milos|M|', 'Christian|Martin|M|', 'Gilbert|Rodney D|RD|', 'Sinha|Manish D|MD|', 'Lord|Graham M|GM|', 'Simpson|Michael|M|', 'Koziell|Ania B|AB|', 'Welsh|Gavin I|GI|', 'Saleem|Moin A|MA|']
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 D040941:Heredity D059014:High-Throughput Nucleotide Sequencing D006801:Humans D007223:Infant D047908:Intracellular Signaling Peptides and Proteins D053208:Kaplan-Meier Estimate D007668:Kidney D007676:Kidney Failure, Chronic D008297:Male D008565:Membrane Proteins D009154:Mutation D009404:Nephrotic Syndrome 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 D055815:Young Adult
nephrotic syndrome cytoskeleton focal segmental glomerulosclerosis pediatric nephrology podocyte proteinuria