NPHS1 – Familial Nephrotic Syndrome

Congenital and familial nephrotic syndrome (MONDO:0002350) is an autosomal recessive disorder presenting within the first 3 months of life with heavy proteinuria, hypoalbuminemia, hyperlipidemia and edema. NPHS1 encodes nephrin, a transmembrane slit-diaphragm protein essential for glomerular filtration. Initial studies showed NPHS1 mutations in nearly all Finnish cases and 39–80% of non-Finnish cohorts, implicating it as the primary gene for congenital nephrotic syndrome ([PMID:22653594]).

Genetic evidence has been amassed in over 300 unrelated probands with biallelic NPHS1 variants across more than 50 families worldwide, including nonsense, frameshift, splice-site, missense, small insertions and deletions ([PMID:39596340]). The variant spectrum comprises >100 distinct alleles: ~65% predicted loss-of-function (e.g., nonsense and frameshift) and ~35% missense substitutions. Founder alleles include the Finnish Fin-major/Fin-minor mutations and the Maori NPHS1 c.2131C>A (p.Arg711Ser) variant in Rapa Nui patients ([PMID:38808020]). A recurrent variant in Chinese and Vietnamese cohorts is c.3250dup (p.Val1084fsTer12) ([PMID:22653594]). Phenotypic variability correlates with allele severity; some missense alleles (e.g., p.Leu587Arg) present later or retain partial steroid responsiveness ([PMID:20172850]).

NPHS1-related disease follows an autosomal recessive inheritance pattern, with at least 19 additional affected relatives demonstrating segregation of pathogenic alleles in multiplex families. Robust functional studies confirm the mechanism of pathogenicity: most missense mutants are misfolded and retained in the endoplasmic reticulum, abrogating cell-surface localization and slit-diaphragm assembly ([PMID:15213260]). Chemical chaperones (e.g., 4-phenylbutyrate) can rescue trafficking defects in vitro. Kidney organoids derived from patient iPSCs recapitulate impaired nephrin localization and slit diaphragm formation, reversible by genetic correction ([PMID:30174315]). A CRISPR/Cas9 zebrafish nphs1 mutant completely lacks nephrin, develops edema, foot process effacement and proteinuria, faithfully modeling human disease ([PMID:36187478]).

Collectively, the concordance of extensive genetic case series, segregation data, and concordant cellular and animal models supports a Definitive ClinGen clinical validity classification. Genetic evidence is Strong, with >300 probands bearing biallelic variants and a broad variant spectrum. Functional evidence is Strong, demonstrating ER retention of mutants, chaperone rescue, patient-derived organoid defects, and animal phenocopy. No substantive refuting evidence has been reported, though mild alleles may lead to delayed onset or partial steroid responsiveness.

Key take-home: NPHS1 testing is essential for diagnosis of congenital nephrotic syndrome, guides prognosis and genetic counseling, and identifies candidates for emerging targeted therapies.

References

• Kidney international • 2000 • Novel mutation in the nephrin gene of a Japanese patient with congenital nephrotic syndrome of the Finnish type PMID:10652016
• Genetics and Molecular Research • 2012 • Mutations in NPHS1 in a Chinese child with congenital nephrotic syndrome PMID:22653594
• Journal of the American Society of Nephrology • 2004 • Defective trafficking of nephrin missense mutants rescued by a chemical chaperone PMID:15213260
• Stem Cell Reports • 2018 • Organoids from Nephrotic Disease-Derived iPSCs Identify Impaired NEPHRIN Localization and Slit Diaphragm Formation in Kidney Podocytes PMID:30174315
• Frontiers in Cell and Developmental Biology • 2022 • A zebrafish model of congenital nephrotic syndrome of the Finnish type PMID:36187478

Evidence Based Scoring (AI generated)