RT Journal Article
T1 A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies.
A1 Gonzalez-Del Pozo, Maria
A1 Fernandez-Suarez, Elena
A1 Bravo-Gil, Nereida
A1 Mendez-Vidal, Cristina
A1 Martin-Sanchez, Marta
A1 Rodriguez-de la Rua, Enrique
A1 Ramos-Jimenez, Manuel
A1 Morillo-Sanchez, Maria Jose
A1 Borrego, Salud
A1 Antiñolo, Guillermo
K1 Genetics research
K1 Hereditary eye disease
K1 Retinal diseases
K1 Translational research
AB To enhance the use of Whole Genome Sequencing (WGS) in clinical practice, it is still necessary to standardize data analysis pipelines. Herein, we aimed to define a WGS-based algorithm for the accurate interpretation of variants in inherited retinal dystrophies (IRD). This study comprised 429 phenotyped individuals divided into three cohorts. A comparison of 14 pathogenicity predictors, and the re-definition of its cutoffs, were performed using panel-sequencing curated data from 209 genetically diagnosed individuals with IRD (training cohort). The optimal tool combinations, previously validated in 50 additional IRD individuals, were also tested in patients with hereditary cancer (n = 109), and with neurological diseases (n = 47) to evaluate the translational value of this approach (validation cohort). Then, our workflow was applied for the WGS-data analysis of 14 individuals from genetically undiagnosed IRD families (discovery cohort). The statistical analysis showed that the optimal filtering combination included CADDv1.6, MAPP, Grantham, and SIFT tools. Our pipeline allowed the identification of one homozygous variant in the candidate gene CFAP20 (c.337 C > T; p.Arg113Trp), a conserved ciliary gene, which was abundantly expressed in human retina and was located in the photoreceptors layer. Although further studies are needed, we propose CFAP20 as a candidate gene for autosomal recessive retinitis pigmentosa. Moreover, we offer a translational strategy for accurate WGS-data prioritization, which is essential for the advancement of personalized medicine.
PB Nature Publishing Group
YR 2022
FD 2022-03-04
LK http://hdl.handle.net/10668/19552
UL http://hdl.handle.net/10668/19552
LA en
NO González-Del Pozo M, Fernández-Suárez E, Bravo-Gil N, Méndez-Vidal C, Martín-Sánchez M, Rodríguez-de la Rúa E, et al. A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies. NPJ Genom Med. 2022 Mar 4;7(1):17.
NO The authors thank the families who participated in this study, the donors and the University Hospital Virgen del Rocio-Institute of Biomedicine of Seville Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for the human specimens used in this study, and the Andalusian Association of Retinitis Pigmentosa (AARP). This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain and co-funded by the European Union (ERDF, “A way to make Europe”) [PI18-00612; PI21-00244], Regional Ministry of Health and Families of the Autonomous Government of Andalusia [PEER-0501-2019] and the Foundation Isabel Gemio/Foundation Cajasol [FGEMIO-2019-01]. EFS is supported by fellowship FI19/00091 from ISCIII (ESF, “Investing in your future”). MMS is supported by a fellowship associated with the CTS-1664 project, which has been funded by the Regional Ministry of Economy, Knowledge, Enterprise, and the University of the Regional Government of Andalusia. NBG is supported by a fellowship RH-0118-2020, which has been funded by the Regional Ministry of Health and Families of the Autonomous Government of Andalusia.
DS RISalud
RD Apr 5, 2025