TY - JOUR
T1 - Noncoding mutation in rpgrip1 contributes to inherited retinal degenerations
AU - Zou, Gang
AU - Zhang, Tao
AU - Cheng, Xuesen
AU - Igelman, Austin D.
AU - Wang, Jun
AU - Qian, Xinye
AU - Fu, Shangyi
AU - Wang, Keqing
AU - Koenekoop, Robert K.
AU - Fishman, Gerald A.
AU - Yang, Paul
AU - Li, Yumei
AU - Pennesi, Mark E.
AU - Chen, Rui
N1 - Funding Information:
We thank the patients and families for their enthusiastic participation. We thank Iris Chen for reading and editing the manuscript. This work is supported by the key research and development program Ningxia Hui Autonomous Region of China (2020B?G03044) to GZ, CIHR, Fighting Blindness Canada, MCH Foundation and Reseau de Vision to RKK, Retinal Research Foundation to RC. Dr. GAF acknowledges funding from the Pangere family. NIH K08?Y026650 to PY. Supported by grant P30?Y010572 from the National Institutes of Health (Bethesda, MD), and by unrestricted
Funding Information:
departmental funding from Research to Prevent Blindness
Funding Information:
We thank the patients and families for their enthusiastic participation. We thank Iris Chen for reading and editing the manuscript. This work is supported by the key research and development program Ningxia Hui Autonomous Region of China (2020BEG03044) to GZ, CIHR, Fighting Blindness Canada, MCH Foundation and Reseau de Vision to RKK, Retinal Research Foundation to RC. Dr. GAF acknowledges funding from the Pangere family. NIH K08EY026650 to PY. Supported by grant P30EY010572 from the National Institutes of Health (Bethesda, MD), and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY).
Publisher Copyright:
© 2021 Molecular Vision.
PY - 2021
Y1 - 2021
N2 - Purpose: Despite the extensive use of next-generation sequencing (NGS) technology to identify disease-causing genomic variations, a major gap in our understanding of Mendelian diseases is the unidentified molecular lesion in a significant portion of patients. For inherited retinal degenerations (IRDs), although currently close to 300 disease-associated genes have been identified, the mutations in approximately one-third of patients remain unknown. With mounting evidence that noncoding mutations might contribute significantly to disease burden, we aimed to systematically investigate the contributions of noncoding regions in the genome to IRDs. Methods: In this study, we focused on RPGRIP1, which has been linked to various IRD phenotypes, including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), and macular dystrophy (MD). As several noncoding mutant alleles have been reported in RPGRIP1, and we observed that the mutation carrier frequency of RPGRIP1 is higher in patient cohorts with unsolved IRDs, we hypothesized that mutations in the noncoding regions of RPGRIP1 might be a significant contributor to pathogenicity. To test this hypothesis, we performed whole-genome sequencing (WGS) for 25 patients with unassigned IRD who carry a single mutation in RPGRIP1. Results: Three noncoding variants in RPGRIP1, including a 2,890 bp deletion and two deep-intronic variants (c.2710+233G>A and c.1468–263G>C), were identified as putative second hits of RPGRIP1 in three patients with LCA. The mutant alleles were validated with direct sequencing or in vitro assays. Conclusions: The results highlight the significance of the contribution of noncoding pathogenic variants to unsolved IRD cases.
AB - Purpose: Despite the extensive use of next-generation sequencing (NGS) technology to identify disease-causing genomic variations, a major gap in our understanding of Mendelian diseases is the unidentified molecular lesion in a significant portion of patients. For inherited retinal degenerations (IRDs), although currently close to 300 disease-associated genes have been identified, the mutations in approximately one-third of patients remain unknown. With mounting evidence that noncoding mutations might contribute significantly to disease burden, we aimed to systematically investigate the contributions of noncoding regions in the genome to IRDs. Methods: In this study, we focused on RPGRIP1, which has been linked to various IRD phenotypes, including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), and macular dystrophy (MD). As several noncoding mutant alleles have been reported in RPGRIP1, and we observed that the mutation carrier frequency of RPGRIP1 is higher in patient cohorts with unsolved IRDs, we hypothesized that mutations in the noncoding regions of RPGRIP1 might be a significant contributor to pathogenicity. To test this hypothesis, we performed whole-genome sequencing (WGS) for 25 patients with unassigned IRD who carry a single mutation in RPGRIP1. Results: Three noncoding variants in RPGRIP1, including a 2,890 bp deletion and two deep-intronic variants (c.2710+233G>A and c.1468–263G>C), were identified as putative second hits of RPGRIP1 in three patients with LCA. The mutant alleles were validated with direct sequencing or in vitro assays. Conclusions: The results highlight the significance of the contribution of noncoding pathogenic variants to unsolved IRD cases.
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M3 - Article
C2 - 33907365
AN - SCOPUS:85105102759
SN - 1090-0535
VL - 27
SP - 95
EP - 106
JO - Molecular vision
JF - Molecular vision
ER -