Pseudodominant inheritance of retinitis pigmentosa in a family with mutations in the Eyes Shut Homolog (EYS) gene.
EYS gene variant
Autosomal recessive retinitis pigmentosa
Copy-number variation
Genetic testing
Inherited retinal dystrophy
Pseudodominant inheritance
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
10 Aug 2024
10 Aug 2024
Historique:
received:
31
03
2024
accepted:
07
08
2024
medline:
11
8
2024
pubmed:
11
8
2024
entrez:
10
8
2024
Statut:
epublish
Résumé
Sequence variants in Eyes Shut Homolog (EYS) gene are one of the most frequent causes of autosomal recessive retinitis pigmentosa (RP). Herein, we describe an Italian RP family characterized by EYS-related pseudodominant inheritance. The female proband, her brother, and both her sons showed typical RP, with diminished or non-recordable full-field electroretinogram, narrowing of visual field, and variable losses of central vision. To investigate this apparently autosomal dominant pedigree, next generation sequencing (NGS) of a custom panel of RP-related genes was performed, further enhanced by bioinformatic detection of copy-number variations (CNVs). Unexpectedly, all patients had a compound heterozygosity involving two known pathogenic EYS variants i.e., the exon 33 frameshift mutation c.6714delT and the exon 29 deletion c.(5927þ1_5928-1)_(6078þ1_6079-1)del, with the exception of the youngest son who was homozygous for the above-detailed frameshift mutation. No pathologic eye conditions were instead observed in the proband's husband, who was a heterozygous healthy carrier of the same c.6714delT variant in exon 33 of EYS gene. These findings provide evidence that pseudodominant pattern of inheritance can hide an autosomal recessive RP partially or totally due to CNVs, recommending CNVs study in those pedigrees which remain genetically unsolved after the completion of NGS or whole exome sequencing analysis.
Identifiants
pubmed: 39127808
doi: 10.1038/s41598-024-69640-9
pii: 10.1038/s41598-024-69640-9
doi:
Substances chimiques
Eye Proteins
0
EYS protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
18580Informations de copyright
© 2024. The Author(s).
Références
Hartong, D. T., Berson, E. L. & Dryja, T. P. Retinitis pigmentosa. Lancet 368, 1795–1809 (2006).
doi: 10.1016/S0140-6736(06)69740-7
pubmed: 17113430
Chizzolini, M. et al. Good epidemiologic practice in retinitis pigmentosa: From phenotyping to biobanking. Curr. Genomics 12, 260–266 (2011).
doi: 10.2174/138920211795860071
pubmed: 22131871
pmcid: 3131733
Ferrari, S. et al. Retinitis pigmentosa: Genes and disease mechanisms. Curr. Genomics 12, 238–249 (2011).
doi: 10.2174/138920211795860107
pubmed: 22131869
pmcid: 3131731
Verbakel, S. K. et al. Non-syndromic retinitis pigmentosa. Prog. Retin. Eye Res. 66, 157–186 (2018).
doi: 10.1016/j.preteyeres.2018.03.005
pubmed: 29597005
Daiger, S. P., Sullivan, L. S., Bowne, S. J. & Rossiter, B. J. F. RetNet
Yu-Wai-Man, P. & Newman, N. J. Inherited eye-related disorders due to mitochondrial dysfunction. Hum. Mol. Genet. 26, R12–R20 (2017).
doi: 10.1093/hmg/ddx182
pubmed: 28481993
pmcid: 6074842
Okazaki, A. & Ott, J. Machine learning approaches to explore digenic inheritance. Trends Genet. 38, 1013–1018 (2022).
doi: 10.1016/j.tig.2022.04.009
pubmed: 35581032
Churchill, J. D. et al. Mutations in the X-linked retinitis pigmentosa genes RPGR and RP2 found in 8.5% of families with a provisional diagnosis of autosomal dominant retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 54, 1411–1416 (2013).
doi: 10.1167/iovs.12-11541
pubmed: 23372056
pmcid: 3597192
Parmeggiani, F. et al. Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia. Sci. Rep. 6, 39179 (2016).
doi: 10.1038/srep39179
pubmed: 27995965
pmcid: 5171904
De Silva, S. R. et al. The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies. Prog. Retin. Eye Res. 82, 100898 (2021).
doi: 10.1016/j.preteyeres.2020.100898
pubmed: 32860923
Ge, Z. et al. NGS-based molecular diagnosis of 105 eyeGENE® probands with retinitis pigmentosa. Sci. Rep. 5, 18287 (2015).
doi: 10.1038/srep18287
pubmed: 26667666
pmcid: 4678898
Habibi, I. et al. Different phenotypes in pseudodominant inherited retinal dystrophies. Front. Cell Dev. Biol. 9, 625560 (2021).
doi: 10.3389/fcell.2021.625560
pubmed: 33634125
pmcid: 7902019
Robles Bocanegra, A., Tato, J., Molina Thurin, L. J., Izquierdo, N. & Oliver, A. L. Pseudodominant inheritance of retinitis pigmentosa due to mutations in the phosphodiesterase 6B gene: A case report. Cureus 15, e34933 (2023).
pubmed: 36938204
pmcid: 10016385
Littink, K. W. et al. Mutations in the EYS gene account for approximately 5% of autosomal recessive retinitis pigmentosa and cause a fairly homogeneous phenotype. Ophthalmology 117, 2026–2033 (2010).
doi: 10.1016/j.ophtha.2010.01.040
pubmed: 20537394
Barragán, I. et al. Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa. Hum. Mutat. 31, E1772–E1800 (2010).
doi: 10.1002/humu.21334
pubmed: 21069908
pmcid: 3045506
Audo, I. et al. EYS is a major gene for rod-cone dystrophies in France. Hum. Mutat. 31, E1406–E1435 (2010).
doi: 10.1002/humu.21249
pubmed: 20333770
Iwanami, M. et al. Five major sequence variants and copy number variants in the EYS gene account for one-third of Japanese patients with autosomal recessive and simplex retinitis pigmentosa. Mol. Vis. 25, 766–779 (2019).
pubmed: 31814702
pmcid: 6857781
Gao, F. J. et al. Genetic and clinical findings in a large cohort of Chinese patients with suspected retinitis pigmentosa. Ophthalmology 126, 1549–1556 (2019).
doi: 10.1016/j.ophtha.2019.04.038
pubmed: 31054281
Marques, J. P. et al. Design, development and deployment of a web-based interoperable registry for inherited retinal dystrophies in Portugal: the IRD-PT. Orphanet J. Rare Dis. 15, 304 (2020).
doi: 10.1186/s13023-020-01591-6
pubmed: 33109251
pmcid: 7590677
Collin, R. W. et al. Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa. Am. J. Hum. Genet. 83, 594–603 (2008).
doi: 10.1016/j.ajhg.2008.10.014
pubmed: 18976725
pmcid: 2668042
Zelhof, A. C., Hardy, R. W., Becker, A. & Zuker, C. S. Transforming the architecture of compound eyes. Nature 443, 696–699 (2016).
doi: 10.1038/nature05128
Abd El-Aziz, M. M. et al. EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Nat. Genet. 40, 1285–1287 (2008).
doi: 10.1038/ng.241
pubmed: 18836446
pmcid: 2719291
Alfano, G. et al. EYS is a protein associated with the ciliary axoneme in rods and cones. PLoS One 11, e0166397 (2016).
doi: 10.1371/journal.pone.0166397
pubmed: 27846257
pmcid: 5112921
Garcia-Delgado, A. B. et al. Dissecting the role of EYS in retinal degeneration: Clinical and molecular aspects and its implications for future therapy. Orphanet J. Rare Dis. 16, 222 (2021).
doi: 10.1186/s13023-021-01843-z
pubmed: 34001227
pmcid: 8127272
Khateb, S. et al. Identification of genomic deletions causing inherited retinal degenerations by coverage analysis of whole exome sequencing data. J. Med. Genet. 53, 600–607 (2016).
doi: 10.1136/jmedgenet-2016-103825
pubmed: 27208209
Soares, R. M. et al. Eyes shut homolog-associated retinal degeneration: Natural history, genetic landscape, and phenotypic spectrum. Ophthalmol. Retina 7, 628–638 (2023).
doi: 10.1016/j.oret.2023.02.001
pubmed: 36764454
McGuigan, D. B. et al. EYS mutations causing autosomal recessive retinitis pigmentosa: Changes of retinal structure and function with disease progression. Genes (Basel) 8, 178 (2017).
doi: 10.3390/genes8070178
pubmed: 28704921
Zampaglione, E. et al. Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations. Genet. Med. 22, 1079–1087 (2020).
doi: 10.1038/s41436-020-0759-8
pubmed: 32037395
pmcid: 7272325
Placidi, G. et al. Retinitis pigmentosa associated with EYS gene mutations: Disease severity staging and central retina atrophy. Diagnostics (Basel) 13, 850 (2023).
doi: 10.3390/diagnostics13050850
pubmed: 36899994
Stone, E. M. et al. Recommendations for genetic testing of inherited eye diseases: Report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology 119, 2408–2410 (2012).
doi: 10.1016/j.ophtha.2012.05.047
pubmed: 22944025
Black, G. C. et al. The need for widely available genomic testing in rare eye diseases: An ERN-EYE position statement. Orphanet J. Rare Dis. 16, 142 (2021).
doi: 10.1186/s13023-021-01756-x
pubmed: 33743793
pmcid: 7980559
Stephenson, K. A. J. et al. Target 5000: A standardized all-Ireland pathway for the diagnosis and management of inherited retinal degenerations. Orphanet J. Rare Dis. 5, 200 (2021).
doi: 10.1186/s13023-021-01841-1
Parmeggiani, F. X-chromosome insight for targeting gene therapy. Ophthalmol. Retina 4, 521–522 (2020).
doi: 10.1016/j.oret.2020.01.005
pubmed: 32381254
Botto, C. et al. Early and late stage gene therapy interventions for inherited retinal degenerations. Prog. Retin. Eye Res. 86, 100975 (2022).
doi: 10.1016/j.preteyeres.2021.100975
pubmed: 34058340
Schneider, N. et al. Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities. Prog. Retin. Eye Res. 89, 101029 (2022).
doi: 10.1016/j.preteyeres.2021.101029
pubmed: 34839010
Park, J. G. et al. Reproductive ophthalmology: The intersection of inherited eye diseases and reproductive technologies. Retina 42, 2025–2030 (2022).
doi: 10.1097/IAE.0000000000003591
pubmed: 35963004
pmcid: 10593127
Chylack, L. T. et al. The lens opacities classification system III. The longitudinal study of Cataract Study Group. Arch. Ophthalmol. 111, 831–836 (1993).
doi: 10.1001/archopht.1993.01090060119035
pubmed: 8512486
Brigell, M., Bach, M., Barber, C., Kawasaki, K. & Kooijman, A. Guidelines for calibration of stimulus and recording parameters used in clinical electrophysiology of vision. Calibration standard Committee of the International Society for Clinical Electrophysiology of Vision (ISCEV). Doc. Ophthalmol. 95, 1–14 (1998).
doi: 10.1023/A:1001724411607
pubmed: 10189178