Novel Mutations in NPHS1 are a Rare Cause of Congenital Nephrotic Syndrome

Congenital Nephrotic Syndrome (CNS) is an autosomal recessive disorder most commonly caused by mutations in NPHS1 which encodes the nephrin protein. It is characterized by massive proteinuria, hypoalbuminemia and gross edema in the neonatal period. This report describes two male siblings of mixed Filipino and German descent who both presented in the neonatal period with CNS. Sequencing of NPHS1 demonstrated a previously unreported novel heterozygous mutation in exon 11 denoted c.1437C>G (p.Y479X). This mutation creates a premature stop codon which is very likely to result in a truncated protein or loss of protein production, and it is therefore likely disease-causing. Additionally a previously unreported novel heterozygous large deletion encompassing exons 25, 26, 27, 28 and 29 of the NPHS1 gene was detected by qPCR. This mutation is very likely to result in loss of protein production, and it is therefore likely disease-causing. We note that long deletions are particularly rare in CNS [4,5], and this could be due to the lack of clinically available testing for deletions in NPHS1 – at this time deletion/duplication analysis is not clinically available in the US. In summary, this report describes two siblings affected with previously undescribed mutations in NPHS1 which are a cause of CNS.