Congenital and infantile nephrotic syndrome: genotype-phenotype associations

Background: Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are disorders of podocytes in the slit diaphragm. CNS manifests during the first three months of life, and INS between 3–12 months, with severe proteinuria due to mutations in the NPHS1 and NPHS2 genes. This study aimed to establish specific genotype-phenotype characteristics of CNS and INS in the North American population. Methods: Eleven Pediatric Nephrology Research Consortium (PNRC) sites retrospectively reviewed charts of 36 patients born between 1998–2019 who had CNS or INS and underwent genetic testing. The genetic database confirmed the variant’s pathogenicity. Results: NPHS1 mutations were more frequently seen in CNS patients, while variant mutations in the WT1 and NPHS2 genes were more common in the INS group. Like c.2335-1 G > A splice mutation, the frequent compound heterozygous mutations of the NPHS1 gene were associated with more severe proteinuria (112.4 ± 135.6 vs. 53.9 ± 57.3). Additionally, NPHS1/WT1 and NPHS1/NPHS2 digenic inheritance featuring biallelic or tri-allelic hits were associated with patient transplantation, regardless of the disease onset. Conclusion: Identification of compound heterozygous mutations in the NPHS1 gene as an indicator of an aggressive course of CNS in infants. This finding could lead to earlier and targeted interventions of patients, through a precision therapeutic approach Impact: Variations at splice sites, particularly the c.2335-1 G > A mutation, alongside compound heterozygous mutations in the gene NPHS1 and digenic inheritance involving both NPHS1/WT1 or NPHS1/ NPHS2 with a triallelic hit, have been linked to a more severe progression of Congenital Nephrotic Syndrome (CNS) in infants. The presence of a variant involving the digenic inheritance of the NPHS1 gene among children in North America suggests earlier indicators for the severity of the kidney disease. This knowledge can transform the management of Congenital Nephrotic Syndrome in children’s healthcare settings, and lead to the development of early diagnosis biomarkers for the disease.