ESPN 50th Annual Meeting

ESPN 2017


 
COLLAGEN (COL4) MUTATIONS IN STEROID-RESISTANT NEPHROTIC SYNDROME (SRNS) IN CHILDREN
LARISA PRIKHODINA 1 Larisa Prikhodina 2 MARINA LEBEDENKOVA 1 SVETLANA PAPIZH 1 ZILIA BASHIROVA 1 PETER SHATALOV 1

1- Research Institute of Pediatrics, Pirogov Russian National Research Medical University
2- Russian Academy of Medical Continuous Postgraduate Education
 
Introduction:

SRNS is a genetically heterogeneous glomerulopathy with a high rate progression to CKD. Mutations in COL4A3-5 genes associated with Alport syndrome (AS) or thin basement membrane nephropathy (TBMN) have been identified in patients with SRNS recently. The aim of the study was to investigate the frequency of COL4A3-5 mutations in children with SRNS by targeted next generating sequencing (NGS).

 

Material and methods:

26 children (9M/17F) with non-familial SRNS were recruited. Renal biopsy revealed FSGS in 22 (84.6%), MCD in 2 (7.7%) and IgAN in 2 (7.7%) patients. A targeted NGS covering 68 genes implicated in SRNS including COL4A3-5 was applied. All identified by NGS pathogenic variants were confirmed by direct Sanger sequencing.

Results:

Mutations in COL4A3-5 genes were identified in 4 out of 26 (15.4%) children with SRNS (Table 1). Three novel sequence variants in COL4A3 and COL4A5 genes were detected with consideration as likely pathogenic by in silico studies and AS autosomal dominant and X-linked was diagnosed. Their phenotypes included haematuria in all SRNS children (familial haematuria in 3 out of 4 patients) without hearing loss or ocular disorders. Kidney biopsy shown FSGS (n=3) and IgAN (n=1). Electron microscopy (EM) revealed histopathological features of AS, including thickening and lamellation of glomerular basement membranes, and diffuse effacement of podocytes foot processes. Immunosuppressive treatment was not effective in 3 SRNS children with COL4A3 and COL4A5 mutations and was stopped. TBMN was diagnosed in one girl with SRNS and IgAN based on identification a previously described pathogenic mutation in COL4A4 gene. At the last follow up 3 SRNS pts with AS due to COL4A3 and COL4A5 mutations were on ACE inhibitors and had isolated non-nephrotic proteinuria with normal kidney function.

Patients / gender

Age

at onset SRNS

(years)
Haematuria (familial)

Histological type of SRNS

(AS features  by EM)
Gene

DNA

(protein)

ID (dbSNP) or novel (*)

Phenotype

 

1.      1. F

 12.5  

+

(+)
 

FSGS

(+)
 

COL4A3

 

c.4743T>G

p.(Phe1581Leu) heterozygous*
 

AS autosomal dominant

1.      2. F

 4.5  

+

(+)
 

IgAN

(NA)