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Genet Med. 2019 Mar;21(3):694-704. doi: 10.1038/s41436-018-0104-7. Epub 2018 Aug 3.

Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.

Author information

1
Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.
4
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute and University of Washington, Department of Pediatrics, Seattle, Washington, USA.
5
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
6
Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. eric_pierce@meei.harvard.edu.
7
Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. kinga_bujakowska@meei.harvard.edu.

Abstract

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.

KEYWORDS:

Inherited retinal degeneration; Intronic pathogenic variants; Noncoding pathogenic variants; RPGRIP1; genome sequencing

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