|Title||Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Jamshidi, F, Place, EM, Mehrotra, S, Navarro-Gomez, D, Maher, M, Branham, KE, Valkanas, E, Cherry, TJ, Lek, M, Macarthur, D, Pierce, EA, Bujakowska, KM|
|Date Published||2019 03|
|Keywords||Adult, Chromosome Mapping, DNA Mutational Analysis, DNA, Intergenic, Female, HEK293 Cells, Humans, Male, Mutation, Pedigree, Proteins, Retinal Degeneration, Whole Exome Sequencing, Whole Genome Sequencing|
PURPOSE: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.
METHODS: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.
RESULTS: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.
CONCLUSION: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC6399075|
|Grant List||UM1 HG008900 / HG / NHGRI NIH HHS / United States |
R01 EY026904 / EY / NEI NIH HHS / United States
R01 EY020902 / EY / NEI NIH HHS / United States
R01 EY012910 / EY / NEI NIH HHS / United States
P30 EY014104 / EY / NEI NIH HHS / United States