Screening of the LAMB2, WT1, NPHS1, and NPHS2 Genes in Pediatric Nephrotic Syndrome

Ali A. Lanewala,Shagufta Khaliq,Madiha Shakoor,Aiysha Abid,Saba Shahid,Seema Hashmi

doi:10.3389/fgene.2018.00214

Abstract

Mutations in the NPHS1, NPHS2, LAMB2, and the WT1 genes are responsible for causing nephrotic syndrome (NS) in two third of the early onset cases. This study was carried out to assess the frequencies of mutations in these genes in a cohort of pediatric NS patients. A total of 64 pediatric familial or sporadic SRNS cases were recruited. Among these, 74% had a disease onset of up to 3 years of age. We found one homozygous frameshift mutation in the NPHS1 gene in one CNS case and two homozygous mutations in the NPHS2 gene. Six mutations in four cases in the LAMB2 gene were also identified. No mutation was detected in the WT1 gene in isolated SRNS cases. LAMB2 gene missense mutations were segregating in NS cases with no extra-renal abnormalities. Analysis of the population genomic data (1000 genome and gnomAD databases) for the prevalence estimation revealed that NS is more prevalent than previously determined from clinical cohorts especially in Asian population compared with overall world populations (prevalence worldwide was 1in 189036 and in South-Asian was 1in 56689). Our results reiterated a low prevalence of mutations in the NPHS1, NPHS2, LAMB2, and WT1 genes in the studied population from Pakistan as compared to some European population that showed a high prevalence of mutations in these genes. This is a comprehensive screening of the genes causing early onset NS in sporadic and familial NS cases suggesting a more systematic and robust approach for mutation identification in all the 45 disease-causing genes in NS in our population is required.

Highlights

Nephrotic syndrome (NS) is a common kidney disorder in children characterized by proteinuria, hematuria, hyperalbuminemia, and hypercholesterolemia
In a large study with isolated sporadic NS occurring within the first year of life, two third of the cases were due to the mutations in the NPHS1, NPHS2, WT1, and LAMB2 genes (Hinkes et al, 2007)
In the first part of the study, 14 earlyonset cases were screened for mutation in the NPHS1 and the NPHS2 genes only

Summary

Introduction

Nephrotic syndrome (NS) is a common kidney disorder in children characterized by proteinuria, hematuria, hyperalbuminemia, and hypercholesterolemia. Mutations in around 45 genes have been associated with familial and sporadic NS (Bierzynska et al, 2015). Several approaches are established for preferential screening of the genes based on the age of onset, inheritance patterns and histopathology. In a large study with isolated sporadic NS occurring within the first year of life, two third of the cases were due to the mutations in the NPHS1, NPHS2, WT1, and LAMB2 genes (Hinkes et al, 2007). Mutations in the NPHS1 and NPHS2 genes together share a large proportion of mutations that cause NS in children. The other two genes, WT1 and LAMB2 have been associated with the syndromic or complex forms (Löwik et al, 2009; Zenker et al, 2009)

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