Deletions Overlapping VCAN Exon 8 Are New Molecular Defects for Wagner Disease.
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.
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Cyril
C
Burin-des-Roziers
Service d'ophtalmologie, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Pierre-Raphael
PR
Rothschild
Service de Génétique Médicale, Hôpital Jacques Monod, Le Havre, France.
Valérie
V
Layet
Institut National de la Santé et de la Recherche Médicale (INSERM), France Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), France Etablissement Français du sang (EFS)-Bretagne, Brest, France.
Jian-Min
JM
Chen
Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.
Tiffany
T
Ghiotti
Service de Biochimie et de Génétique Moléculaire, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France.
Céline
C
Leroux
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Frans P M
FP
Cremers
Service d'ophtalmologie, Groupe Hospitalier Cochin-Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Antoine P
AP
Brézin
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Laboratoire de Génétique Moléculaire, Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Sophie
S
Valleix
D056905:Chromosome Breakpoints; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000175:diagnosis* / Q000235:genetics*; D017384:Sequence Deletion; D014178:Translocation, Genetic; D053675:Versicans / Q000172:deficiency* / Q000235:genetics
C508322:VCAN protein, human; D053675:Versicans
VCAN; Wagner disease; deletion; next-generation sequencing; somatic mosaicism; vitreoretinopathy