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

TLDR

Let's craft. Sentence 1: "Mutations in NPHS1, NPHS2, WT1, and LAMB2 are known causes of infant nephrotic syndrome, but their relative prevalence in early‑onset cases is unknown." Sentence 2: "The study aimed to jointly analyze these four genes in a large European cohort of infants with nephrotic syndrome to determine genotype‑phenotype correlations." Sentence 3: "Genetic testing involved direct exon sequencing of NPHS1, NPHS2, and WT1 exons 8–9, with LAMB2 screened by enzymatic mismatch cleavage." Sentence 4: "Mutations were identified in 66.3% of families, explaining 84.8% of congenital and 44.1% of infantile cases; NPHS2 was most frequent, NPHS1 only in congenital cases, and none of the 28 mutation‑positive children responded to steroids, indicating that two thirds of early‑onset nephrotic syndrome can be attributed to these genes and that steroid treatment is largely ineffective, pointing to additional unknown genes." Check length: It's long but still one sentence. Might be okay. Ensure no semicolons?

Abstract

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.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.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.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.