Next-Generation Sequencing for Congenital Nephrotic Syndrome: A Multi-Center Cross-Sectional Study from India

Information on etiology of congenital nephrotic syndrome in non-Caucasian populations is limited. This study aimed to determine the genetic basis of congenital nephrotic syndrome in Indian patients.

In this observational, cross-sectional study, whole exome sequencing was performed on samples from all children diagnosed with congenital nephrotic syndrome, presenting at centers collaborating in a nationwide registry and biorepository. Analysis was targeted to focus on reported or novel, pathogenic or likely pathogenic variants in 89 genes implicated in etiology of nephrotic syndrome. Sanger sequencing was used to confirm disease-causing variants in patients and allelic segregation of compound heterozygous variants in samples from parents. Inheritance of a shared haplotype was analyzed among ten individuals carrying the most common variant.

During 2017-2019, 34 patients with congenital nephrotic syndrome were screened. Consanguinity and similar illness in siblings were reported in eleven patients each. Homozygous or compound heterozygous, pathogenic or likely pathogenic variants were found in NPHS1 in 24 cases, including two novel variants. One patient each had homozygous pathogenic or likely pathogenic known or novel variant in NPHS2, PLCE1, OSGEP and LAMB2 genes. Patients with OSGEP and LAMB2 mutations had phenotype typical of Galloway Mowat and Pierson syndromes, respectively. Three variants in NPHS1 were common to 16 individuals. One reported variant in exon 19 (c.2600G>A; p.Gly867Asp) appears to share a common founder.

A genetic cause was determined for 82.4% patients with congenital nephrotic syndrome. Variants in NPHS1 are most common in Indian patients and founder mutations might be present.