MP837
LAMA5 VARIANTS IN CHILDHOOD STEROID-RESISTANT NEPHROTIC SYNDROME: CANDIDATE GENE MUTATIONS OR INCIDENTAL FINDINGS?

INTRODUCTION AND AIMS: Steroid-resistant nephrotic syndrome (SRNS) is genetically heterogeneous kidney disease and one of the leading causes of end-stage renal disease in childhood. Laminin, encoded by laminin subunit alpha 5 gene (LAMA5; OMIM *601033), is one of the main component of glomerular basement membranes, necessary for final glomerular maturation and maintenance of filtration barrier properties. The aim of the study was to evaluate clinical utility of LAMA5 variants in children with sporadic SRNS identified by targeted next generating exom sequencing (NGS).

METHODS: The mutational analysis was performed in 15 children (4M/11F) with primary non-familial SRNS. The mean age at onset of disease was 5.0 (IQR: 3.0; 9.5) years. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 12 (80%), minimal change disease (MCD) in 2 (13.3%), membranous nephropathy (MN) in 1 (6.7%) patients. Baseline eGFR was >90 m1/min/1.73 m² in all SRNS patients. NGS of 68 SRNS genes was performed using Illumina’s platform with confirmation all identified variants by Sanger sequencing.

RESULTS: NGS analysis identified heterozygous likely pathogenic missense mutations in LAMA5 gene in 3/15 (20%) children with morphologically heterogeneous SRNS (Table 1). LAMA5 mutations were the only ones identified mutations in SRNS children #1 and #2 and combined with homozygous pathogenic CLDN mutation c.3890C>T in patient #3. Immunosuppressive treatment with calcineurin inhibitors induced complete remission in all 3 patients with LAMA5 mutations. eGFR was >90 m1/min/1.73 m² at the last follow up in all SRNS patients .

CONCLUSIONS:LAMA5 mutations were one of the most prevalent gene mutations identified in 20% children with SRNS by NGS. Despite the fact that we could not find any genotype-phenotype associations in SRNS patients, we assume that LAMA5 mutations might have modifier effects and can contribute to the phenotype of the disease that requires further segregation/functional studies to confirm their pathogenic potential.