Deletions Overlapping VCAN Exon 8 Are New Molecular Defects for Wagner Disease

ABSTRACT Wagner disease is a rare nonsyndromic autosomal‐dominant vitreoretinopathy, associated with splice mutations specifically targeting VCAN exon 8. We report the extensive genetic analysis of two Wagner probands, previously found negative for disease‐associated splice mutations. Next‐generation sequencing (NGS), quantitative real‐time PCR, and long‐range PCR identified two deletions (3.4 and 10.5 kb) removing at least one exon–intron boundary of exon 8, and both correlating with an imbalance of VCAN mRNA isoforms. We showed that the 10.5‐kb deletion occurred de novo, causing somatic mosaicism in the proband's mother who had an unusually mild asymmetrical phenotype. Therefore, exon 8 deletions are novel VCAN genetic defects responsible for Wagner disease, and VCAN mosaic mutations may be involved in the pathogenesis of Wagner disease with attenuated phenotype. NGS is then an effective screening tool for genetic diagnosis of Wagner disease, improving the chance of identifying all disease‐causative variants as well as mosaic mutations in VCAN. Next generation sequencing technology (NGS) reveals heterozygous genomic deletions overlapping VCAN exon 8 explaining unsolved Wagner patients found negative for exon 8 splice mutations. NGS also detects somatic mosaicism of a 10.5‐kb exon 8 deletion in a sporadic Wagner case who presented an unusually asymetrical ocular phenotype. NGS technology is therefore an efficient tool to identify all VCAN disease‐causative variants in heterozygous or mosaic state, and is warranted even in patients with a suspected Wagner phenotype without familial history.