title: Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).
abstract: OBJECTIVE
  Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations.
  
  
  METHODS
  We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage.
  
  
  RESULTS
  We detected disease-causing mutations in 66.3% (53 of 80) families (NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment.
  
  
  CONCLUSIONS
  First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only (NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.
authors: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors: Bernward G
authors: BG
authors: Hinkes
authors: Bettina
authors: B
authors: Mucha
authors: Christopher N
authors: CN
authors: Vlangos
authors: Rasheed
authors: R
authors: Gbadegesin
authors: Jinhong
authors: J
authors: Liu
authors: Katrin
authors: K
authors: Hasselbacher
authors: Daniela
authors: D
authors: Hangan
authors: Fatih
authors: F
authors: Ozaltin
authors: Martin
authors: M
authors: Zenker
authors: Friedhelm
authors: F
authors: Hildebrandt
mesh_terms: D000367:Age Factors; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005838:Genotype; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009404:Nephrotic Syndrome / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D018570:Risk Assessment; D025721:WT1 Proteins / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D025721:WT1 Proteins