title: DNA copy number variants: A potentially useful predictor of early onset renal failure in boys with posterior urethral valves.
abstract: BACKGROUND
  Posterior urethral valves (PUV) are among the most common urological causes of chronic kidney disease (CKD) in childhood. Recently, genomic imbalances have been cited as potential risk factors for altered kidney function and have been associated with CKD. The phenotypic effects of a copy number variant (CNV) in boys with PUV are unknown. Here, it was hypothesised that the progression to early renal failure in PUV patients may be influenced by genetic aberrations.
  
  
  OBJECTIVE
  To assess the relationship between CNVs and renal outcomes.
  
  
  METHODS
  Between September 2012 and July 2015, 45 children with PUV were recruited to evaluate the presence of CNVs in their DNA. The patients' medical records were retrospectively reviewed. The criteria for outcomes of renal function included: assessments of the nadir serum creatinine in the first year of life, the estimated glomerular filtration rate at 1 and 5 years, and the requirement for renal replacement.
  
  
  RESULTS
  Thirteen CNVs were identified in 12 boys (29% of the cohort). Microarray analysis revealed two pathogenic CNVs (well-established CNVs known to be associated with genetic disease) and 11 of unknown significance (CNVs with insufficient current available evidence for unequivocal determination of clinical significance), including genes that have been previously implicated in kidney diseases and urogenital disorders. The median follow-up was 10.2 years (range 3-17.5) in the group of patients with CNV compared with 5.8 years (range 1-16.6) in those CNV-. The nadir creatinine values were significantly higher in boys with CNVs than in those without CNVs (57.5 μmol/L (range 23-215) and 28 μmol/L (range 18-155), respectively (P = 0.05) (Figure). Boys CNV+ had a worse prognosis, with a higher incidence of Stage-V CKD compared with the control group (33% with CNVs vs. 9% in CNV-, P = 0.06) at a median age of 22 months (range 8 months-16 years). Four (33%) patients CNV+ underwent renal transplantation.
  
  
  CONCLUSIONS
  The role of CNVs in the deterioration of renal function remains unknown. It can be hypothesised that CNVs could be a contributing factor or may serve as an accelerant for the progression to renal failure.
  
  
  CONCLUSIONS
  The CNVs >100 Kb were significantly associated with early onset renal failure in children with PUV. Prenatal detection of CNV could help to identify foetuses at high risk of severe renal impairment in cases of suspected PUV, especially in cases without oligohydramnios or severe pulmonary hypoplasia. These preliminary results should be confirmed in a larger cohort of patients.
authors.affiliation: Department of Urology, Royal Children's Hospital, Parkville, VIC 3052, Australia. Electronic address: alice.faure@ap-hm.fr.
authors.forename: A
authors.initials: A
authors.lastname: Faure
authors.affiliation: Department of Urology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Bouty
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Caruana
authors.affiliation: Royal Children's Hospital, VCGS, Parkville, VIC 3052, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Williams
authors.affiliation: Royal Children's Hospital, VCGS, Parkville, VIC 3052, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Burgess
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: M N
authors.initials: MN
authors.lastname: Wong
authors.affiliation: Royal Children's Hospital, VCGS, Parkville, VIC 3052, Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: James
authors.affiliation: Department of Urology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: M
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: Department of Paediatric Nephrology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Walker
authors.affiliation: Development and Stem Cells Program, Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Bertram
authors.affiliation: Department of Urology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Heloury
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D018450:Disease Progression; D006801:Humans; D007223:Infant; D008297:Male; D011237:Predictive Value of Tests; D051437:Renal Insufficiency / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics*; D012189:Retrospective Studies; D014521:Urethra / Q000002:abnormalities*; D014522:Urethral Diseases / Q000150:complications
keywords: Boys; Chronic kidney disease; Copy number variant; Nadir creatinine; Posterior urethral valves