Journal
GENETICS IN MEDICINE
Volume 22, Issue 6, Pages 1079-1087Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-020-0759-8
Keywords
inherited retinal degeneration; retinitis pigmentosa; rod-cone dystrophy; cone-rod dystrophy; copy-number variation
Categories
Funding
- National Eye Institute [R01EY012910, R01EY026904, P30EY014104]
- Foundation Fighting Blindness [EGI-GE-1218-0753-UCSD]
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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.
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