Journal
HUMAN MOLECULAR GENETICS
Volume 29, Issue 6, Pages 967-979Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddaa016
Keywords
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Funding
- National Eye Institute [R01EY012910, R01EY026904, P30EY014104]
- Foundation Fighting Blindness [EGI-GE-1218-0753-UCSD, BRGE-1213-0632-UWI]
- National Institute of Child Health and Human Development [U54HD090256]
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Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful, an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient-induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) transcriptome analysis. With this approach, we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.
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