title: Copy-number variation is an important contributor to the genetic causality of inherited retinal degenerations.
abstract: Despite substantial progress in sequencing, current strategies can genetically solve only approximately 55-60% of inherited retinal degeneration (IRD) cases. This can be partially attributed to elusive mutations in the known IRD genes, which are not easily identified by the targeted next-generation sequencing (NGS) or Sanger sequencing approaches. We hypothesized that copy-number variations (CNVs) are a major contributor to the elusive genetic causality of IRDs.
  
  
  
  Twenty-eight cases previously unsolved with a targeted NGS were investigated with whole-genome single-nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) arrays.
  
  
  
  Deletions in the IRD genes were detected in 5 of 28 families, including a de novo deletion. We suggest that the de novo deletion occurred through nonallelic homologous recombination (NAHR) and we constructed a genomic map of NAHR-prone regions with overlapping IRD genes. In this article, we also report an unusual case of recessive retinitis pigmentosa due to compound heterozygous mutations in SNRNP200, a gene that is typically associated with the dominant form of this disease.
  
  
  
  CNV mapping substantially increased the genetic diagnostic rate of IRDs, detecting genetic causality in 18% of previously unsolved cases. Extending the search to other structural variations will probably demonstrate an even higher contribution to genetic causality of IRDs.Genet Med advance online publication 13 October 2016.
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kinga M
authors.initials: KM
authors.lastname: Bujakowska
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rosario
authors.initials: R
authors.lastname: Fernandez-Godino
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Emily
authors.identifier: 0000-0002-1748-5644
authors.initials: E
authors.lastname: Place
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Consugar
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Navarro-Gomez
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.identifier: 0000-0001-5017-5050
authors.initials: J
authors.lastname: White
authors.affiliation: Ophthalmic Genetics &Visual Electrophysiology, Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Emma C
authors.identifier: 0000-0003-3064-2488
authors.initials: EC
authors.lastname: Bedoukian
authors.affiliation: Ophthalmic Genetics &Visual Electrophysiology, Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of BioMedical Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Hongbo M
authors.identifier: 0000-0003-2223-0029
authors.initials: HM
authors.lastname: Xie
authors.affiliation: Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.affiliation: Ophthalmic Genetics &Visual Electrophysiology, Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Ophthalmology &Center for Medical Genetics, Ghent University Hospital &Ghent University, Ghent, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
mesh_terms: D000293:Adolescent; D002648:Child; D002874:Chromosome Mapping; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D016678:Genome; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012162:Retinal Degeneration / Q000235:genetics*