Published online March 19, 2007
PEDIATRICS Vol. 119 No. 4 April 2007, pp. e907-e919 (doi:10.1542/peds.2006-2164)

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ARTICLE

Nephrotic Syndrome in the First Year of Life: Two Thirds of Cases Are Caused by Mutations in 4 Genes (NPHS1, NPHS2, WT1, and LAMB2)

Bernward G. Hinkes, MD^a, Bettina Mucha, MD^a, Christopher N. Vlangos, PhD^a, Rasheed Gbadegesin, MD, FAAP^a, Jinhong Liu, MD^a, Katrin Hasselbacher^a, Daniela Hangan, MD^a, Fatih Ozaltin, MD^b, Martin Zenker, MD^c, Friedhelm Hildebrandt, MD^a and members of the Arbeitsgemeinschaft für Paediatrische Nephrologie Study Group

^a Departments of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, Michigan
^b Department of Pediatrics, Hacettepe University, Ankara, Turkey
^c Department of Human Genetics, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany

OBJECTIVES. 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.

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Key Words: nephrotic syndrome • LAMB2 • NPHS1 • NPHS2 • WT1

Abbreviations: NS—nephrotic syndrome • NSFL—nephrotic syndrome manifesting in the first year of life • CNS—congenital nephrotic syndrome • INS—infantile nephrotic syndrome • OMIM—Online Mendelian Inheritance in Man • ESRD—end-stage renal disease

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Accepted Oct 18, 2006.

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