Whole-Genome Sequencing in Diagnostics of Unsolved Cases of Inherited Retinal Diseases
- 1Research Centre for Medical Genetics, 115522 Moscow, Russia
- 2Biotech Campus Limited Liability Company, 117437 Moscow, Russia
Abstract
The study purpose was to assess the diagnostic value of whole-genome sequencing (WGS) in identifying candidate genetic variants in patients with inherited retinal diseases (IRDs). We investigated 107 unrelated Russian patients with retinal diseases who carried single pathogenic variants in any of nine common autosomal recessive IRD genes (ABCA4, USH2A, EYS, CRB1, RPE65, CNGB3, CNGA3, CEP290, and GUCY2D). WGS was performed for all patients; candidate splice variants were functionally validated using minigene assays. The total diagnostic yield was 40.2% (43/107). In 25.2% of cases (27/107), the diagnosis was established by identifying a second variant in one of the following candidate genes: EYS (n = 9), USH2A (n = 8), ABCA4 (n = 5), CNGB3 (n = 3), CRB1 and CEP290 (n = 1 each). In 15.0% of cases (16/107), the diagnosis was reclassified by variants in alternative IRD genes (autosomal dominant, X-linked, mitochondrial, or syndromic). The majority of second variants detected in AR cases were CNVs (55.5%, 15 patients), followed by non-coding variants (26.0%, seven), structural rearrangements (14.8%, four) and exonic point variant (3.7%, one). Two recurrent CNVs were observed: a gross deletion of exons 22–24 in USH2A (n = 4) and a deletion partially affecting exon 19 of EYS (n = 4). Structural variants were mostly represented by delINV rearrangements (n = 5). Minigene assays confirmed that three novel deep intronic variants (in CHM, EYS, and CEP290) and one non-canonical splice-acceptor variant in USH2A which disrupt splicing, causes pseudoexon inclusion with premature termination or in-frame exon skipping respectively. Thus, WGS improves the diagnostic yield in IRDs by detecting variants missed by targeted sequencing, supporting its clinical utility in ophthalmologic practice.
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BibTeX
@article{ogorodova2026wholegenome,
title = {{Whole-Genome Sequencing in Diagnostics of Unsolved Cases of Inherited Retinal Diseases}},
author = {Natalya Ogorodova and Anna Stepanova and Polina Geletskaia and Vitaly Kadyshev and Rena Zinchenko and Svetlana Kuznetsova and Olga Khalanskaya and Alexandra Monakhova and Nikita Beskorovainy and Victoria Zabnenkova and Oksana Ryzhkova and Konstantin Severinov and Igor Bychkov and Alexander Polyakov and Sergey Kutsev and Olga Shchagina},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209022},
url = {https://www.mdpi.com/1422-0067/27/20/9022},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Whole-Genome Sequencing in Diagnostics of Unsolved Cases of Inherited Retinal Diseases
AU - Natalya Ogorodova
AU - Anna Stepanova
AU - Polina Geletskaia
AU - Vitaly Kadyshev
AU - Rena Zinchenko
AU - Svetlana Kuznetsova
AU - Olga Khalanskaya
AU - Alexandra Monakhova
AU - Nikita Beskorovainy
AU - Victoria Zabnenkova
AU - Oksana Ryzhkova
AU - Konstantin Severinov
AU - Igor Bychkov
AU - Alexander Polyakov
AU - Sergey Kutsev
AU - Olga Shchagina
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209022
UR - https://www.mdpi.com/1422-0067/27/20/9022
AB - The study purpose was to assess the diagnostic value of whole-genome sequencing (WGS) in identifying candidate genetic variants in patients with inherited retinal diseases (IRDs). We investigated 107 unrelated Russian patients with retinal diseases who carried single pathogenic variants in any of nine common autosomal recessive IRD genes (ABCA4, USH2A, EYS, CRB1, RPE65, CNGB3, CNGA3, CEP290, and GUCY2D). WGS was performed for all patients; candidate splice variants were functionally validated using minigene assays. The total diagnostic yield was 40.2% (43/107). In 25.2% of cases (27/107), the diagnosis was established by identifying a second variant in one of the following candidate genes: EYS (n = 9), USH2A (n = 8), ABCA4 (n = 5), CNGB3 (n = 3), CRB1 and CEP290 (n = 1 each). In 15.0% of cases (16/107), the diagnosis was reclassified by variants in alternative IRD genes (autosomal dominant, X-linked, mitochondrial, or syndromic). The majority of second variants detected in AR cases were CNVs (55.5%, 15 patients), followed by non-coding variants (26.0%, seven), structural rearrangements (14.8%, four) and exonic point variant (3.7%, one). Two recurrent CNVs were observed: a gross deletion of exons 22–24 in USH2A (n = 4) and a deletion partially affecting exon 19 of EYS (n = 4). Structural variants were mostly represented by delINV rearrangements (n = 5). Minigene assays confirmed that three novel deep intronic variants (in CHM, EYS, and CEP290) and one non-canonical splice-acceptor variant in USH2A which disrupt splicing, causes pseudoexon inclusion with premature termination or in-frame exon skipping respectively. Thus, WGS improves the diagnostic yield in IRDs by detecting variants missed by targeted sequencing, supporting its clinical utility in ophthalmologic practice.
SN - 1422-0067
ER -