domingo, 29 de enero de 2017

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

2017 Jan 20. pii: S0085-2538(16)30612-3. doi: 10.1016/j.kint.2016.10.013. [Epub ahead of print]

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

Bierzynska A1, McCarthy HJ1, Soderquest K2, Sen ES1, Colby E1, Ding WY1, Nabhan MM3, Kerecuk L4, Hegde S5, Hughes D6, Marks S7, Feather S8, Jones C9, Webb NJ10, Ognjanovic M11, Christian M12, Gilbert RD13, Sinha MD14, Lord GM2, Simpson M15, Koziell AB2, Welsh GI1, Saleem MA16.

Author information

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.