Academic Journal
Diagnostic discovery of structural variants causing foveal hypoplasia using SVRare and long-read nanopore sequencing.
| Τίτλος: | Diagnostic discovery of structural variants causing foveal hypoplasia using SVRare and long-read nanopore sequencing. |
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| Συγγραφείς: | Derar MAM; Division of Molecular Medicine, Leeds Institute of Medical Research, Leeds, UK., Yu J; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK., Watson CM; Division of Molecular Medicine, Leeds Institute of Medical Research, Leeds, UK.; North East and Yorkshire Genomic Laboratory Hub, Central Lab, St. James's University Hospital, Leeds, UK., McKibbin M; Division of Molecular Medicine, Leeds Institute of Medical Research, Leeds, UK.; Department of Ophthalmology, St. James's University Hospital, Leeds, UK., Bell SM; Division of Molecular Medicine, Leeds Institute of Medical Research, Leeds, UK., Inglehearn CF; Division of Molecular Medicine, Leeds Institute of Medical Research, Leeds, UK. c.inglehearn@leeds.ac.uk., Toomes C; Division of Molecular Medicine, Leeds Institute of Medical Research, Leeds, UK. |
| Πηγή: | European journal of human genetics : EJHG [Eur J Hum Genet] 2026 Oct; Vol. 34 (10), pp. 1493-1502. Date of Electronic Publication: 2026 Jul 20. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9302235 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5438 (Electronic) Linking ISSN: 10184813 NLM ISO Abbreviation: Eur J Hum Genet Subsets: MEDLINE |
| Imprint Name(s): | Publication: <2003->: London : Nature Publishing Group Original Publication: Basel ; New York : Karger, [1992- |
| Ιατρικοί όροι (MeSH): | Fovea Centralis*/abnormalities , Fovea Centralis*/pathology , Nanopore Sequencing*/methods , Nanopore Sequencing*/standards , Eye Diseases, Hereditary*/genetics , Eye Diseases, Hereditary*/diagnosis , Genetic Testing*/methods , Genetic Testing*/standards , Eye Abnormalities*/genetics , Eye Abnormalities*/diagnosis , Genomic Structural Variation*, Eye Proteins/genetics ; PAX6 Transcription Factor/genetics ; Membrane Glycoproteins/genetics ; Membrane Transport Proteins/genetics ; Humans ; Female ; Male ; Nystagmus, Congenital ; Amino Acid Transport Systems, Neutral |
| Περίληψη: | Advances in DNA sequencing technology are increasing the rate of molecular diagnosis for patients and families with inherited Mendelian diseases. However, some patients remain unsolved following standard-of-care testing (typically either exome or genome sequencing), with structural variants (SVs) likely to account for a significant proportion of these missed diagnoses. We re-analysed ten research cases with the visual disorder foveal hypoplasia (FH) that were previously unsolved through whole exome sequencing (WES). We used SVRare, a tool that integrates outputs from Canvas and Manta and combines these with allele frequencies and information regarding their genomic context to highlight plausible pathogenic SVs. This analysis solved 2/10 cases. Expanding this strategy, we then used SVRare in a reverse genetics approach to analyse an FH-relevant gene panel in the 100,000 Genomes Project (100KGP) rare disease cohort. This identified potentially pathogenic SVs as the cause of disease in a further 11 previously unsolved cases with phenotypes overlapping FH. In total, 11 SVs in five genes were identified as the likely cause of FH in 13 patients: SLC38A8 (1 patient), PAX6 (3), OCA2 (3), GPR143 (5) and CACNA1F (1). This analysis also identified multiple carriers of an apparently novel deletion in OCA2. However, further analysis suggested that this is, in fact, the relatively common founder variant responsible for oculocutaneous albinism (OCA) in African populations, first identified over 30 years ago. These findings show that SVRare effectively identifies deleterious SVs and illustrates the challenges in reporting SVs, including the importance of accurate and consistent reporting of such variants. (© 2026. The Author(s).) |
| Competing Interests: | Competing interests: The authors declare no competing interests. Ethical approval: Informed and written consent was provided by all patients in accordance with the principles of the Declaration of Helsinki. Ethical approval for this project was granted by the Leeds East Teaching Hospitals National Health Service Trust Research Ethics Committee (Project number 17/YH/0032). The 100KGP is covered by REC reference approval 14/EE/1112. |
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| Substance Nomenclature: | 0 (Eye Proteins) 0 (PAX6 Transcription Factor) 0 (Membrane Glycoproteins) 0 (OCA2 protein, human) 0 (PAX6 protein, human) 0 (Slc38a8 protein, human) 0 (Membrane Transport Proteins) 0 (GPR143 protein, human) 0 (Amino Acid Transport Systems, Neutral) |
| SCR Disease Name: | Foveal Hypoplasia, Isolated |
| Entry Date(s): | Date Created: 20260720 Date Completed: 20261003 Latest Revision: 20261006 |
| Update Code: | 20261006 |
| PubMed Central ID: | PMC13634048 |
| DOI: | 10.1038/s41431-026-02190-y |
| PMID: | 42477408 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1476-5438 |
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| DOI: | 10.1038/s41431-026-02190-y |