Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

Genet Med. 2020 Jun;22(6):1079-1087. doi: 10.1038/s41436-020-0759-8. Epub 2020 Feb 10.


Purpose: Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be attributed to elusive pathogenic variants (PVs) in known IRD genes, including copy-number variations (CNVs), which have been shown as major contributors to unsolved IRD cases.

Methods: Five hundred IRD patients were analyzed with targeted next-generation sequencing (NGS). The NGS data were used to detect CNVs with ExomeDepth and gCNV and the results were compared with CNV detection with a single-nucleotide polymorphism (SNP) array. Likely causal CNV predictions were validated by quantitative polymerase chain reaction (qPCR).

Results: Likely disease-causing single-nucleotide variants (SNVs) and small indels were found in 55.6% of subjects. PVs in USH2A (11.6%), RPGR (4%), and EYS (4%) were the most common. Likely causal CNVs were found in an additional 8.8% of patients. Of the three CNV detection methods, gCNV showed the highest accuracy. Approximately 30% of unsolved subjects had a single likely PV in a recessive IRD gene.

Conclusion: CNV detection using NGS-based algorithms is a reliable method that greatly increases the genetic diagnostic rate of IRDs. Experimentally validating CNVs helps estimate the rate at which IRDs might be solved by a CNV plus a more elusive variant.

Keywords: cone–rod dystrophy; copy-number variation; inherited retinal degeneration; retinitis pigmentosa; rod–cone dystrophy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Copy Number Variations / genetics
  • Eye Proteins / genetics
  • Genes, Recessive
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Retinal Degeneration* / diagnosis
  • Retinal Degeneration* / genetics
  • Virulence


  • EYS protein, human
  • Eye Proteins
  • RPGR protein, human