期刊
KIDNEY INTERNATIONAL
卷 91, 期 4, 页码 937-947出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2016.10.013
关键词
cytoskeleton; focal segmental glomerulosclerosis; nephrotic syndrome; pediatric nephrology; podocyte; proteinuria
资金
- Kids Kidney Research, Kidney Research UK
- British Kidney Patient Association
- North Bristol National Health Service Trust
- Nephrotic Syndrome Trust (NeST)
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
- European Renal Association European Dialysis and Transplant Association (ERA EDTA)
- Kidney Research UK (KRUK)
- British Kidney Patients Association (BKPA)
- MRC [G0800571, MR/L002418/1] Funding Source: UKRI
- Kidney Research UK [RP45/2008] Funding Source: researchfish
- Medical Research Council [MR/L002418/1, MR/K500999/1, MR/J006742/1, G0800571] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10074] Funding Source: researchfish
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 nonmonogenic 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.
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