O86
NEXT GENERATION SEQUENCING OF >30 GENES ASSOCIATED WITH STEROID
RESISTANT NEPHROTIC SYNDROME
Agnieszka Bierzynska1, Hugh J. McCarthy1, Michael Simpson3, Ania Koziell3, Denis A.
Baird2, Ian N. Day2, Gavin I. Welsh1, Moin A. Saleem1
1.Academic Renal Unit, University of Bristol; 2. School of Social and Community Medicine,
University of Bristol; 3. Genomic Medicine Group, Kings College London
INTRODUCTION: Up to 95% of children presenting with Steroid Resistant Nephrotic Syndrome
(SRNS) in early life will have a pathogenic single gene mutation in one of over 30 genes currently
associated with this disease. Little is known of the effect of polymorphic variants. We followed up
our previous findings that the increasing reliability of Next Generation Sequencing (NGS) provides
the potential for revolutionising genetic investigation of this and similar patient groups.
METHODS: We used exome sequencing to screen 100 paediatric SRNS patients for genes known
to be associated with hereditary SRNS as well as to look for novel polymorphic variants in other
genes, potentially involved in the disease. Patients were collected via a national UK Renal Registry
with comprehensive detail of phenotype. Significant variants detected by NGS were confirmed by
conventional Sanger sequencing.
RESULTS: 21 patients had either previously described mutation or a variant likely to be disease
causing. Analysis revealed known as well as novel disease associated variations in routinely tested
genes such as NPHS1, NPHS2 and WT1 as well as in other, less common, gene such as MYO1E or
recently identified ADCK4. A phenotypically unexpected mutations were COL4A5 (hemizygous
missense) in a patient without hearing loss and a TRPC6 in patient presented at age of 8 years.
Increased burden of R229Q (NPHS2), R310Q (ACTN4) as well as other rare variants were noted in
known SRNS genes in cases versus controls.
CONCLUSION: Our results demonstrate the obvious clinical need for sequencing multiple genes
in SRNS where genetic heterogeneity is a defining feature.