As the discovery of new genes causing inherited retinal disease (IRD) has plateaued, we look to other factors which could be used to maximize diagnostic yield. We analyzed whole-exome sequencing (WES) data from 506 IRD probands, focusing on the interplay between diagnostic yield, age of symptom onset or diagnosis, family history, and initial clinical diagnosis. The cohort's overall diagnostic yield was 49.2%. Diagnostic yield was negatively correlated with the age of symptom onset and positively correlated with the number of affected family members. Diseases with distinctive clinical presentations such as Bietti crystalline dystrophy (BCD) or Leber congenital amaurosis (LCA) were more reliably diagnosed than more common and heterogeneous diseases like retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). Recurrent genes and variants in this Chinese-majority cohort resemble those found in Chinese cohort studies but differ from populations of European descent, with implications for the design and prioritization of gene therapies. These insights may help optimize the diagnostic utility of genetic testing for IRDs, enhance the delivery of genetic counseling for patients, and guide the development of more inclusive targeted therapies.
References
Ben-Yosef T. Inherited retinal diseases. Int J Mol Sci. 2022;23:13467.
[PMID: 36362249]
Chay J, Tang RWC, Tan TE, Chan CM, Mathur R, Lee BJH, et al. The economic burden of inherited retinal disease in Singapore: a prevalence-based cost-of-illness study. Eye. 2023.; https://doi.org/10.1038/s41433-023-02624-7 .
Lin S, Vermeirsch S, Pontikos N, Martin-Gutierrez MP, Varela MD, Malka, S et al. Spectrum of genetic variants in the commonest genes causing inherited retinal disease in a large molecularly characterised UK cohort. Ophthalmol Retina. 2024; https://doi.org/10.1016/j.oret.2024.01.012 .
Britten-Jones AC, Gocuk SA, Goh KL, Huq A, Edwards TL, Ayton LN. The diagnostic yield of next generation sequencing in inherited retinal diseases: a systematic review and meta-analysis. Am J Ophthalmol. 2023;249:57���73.
[PMID: 36592879]
Huang X-F, Huang F, Wu K-C, Wu J, Chen J, Pang C-P, et al. Genotype���phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. Genet Med. 2015;17:271���8.
[PMID: 25356976]
Wang L, Zhang J, Chen N, Wang L, Zhang F, Ma Z, et al. Application of whole exome and targeted panel sequencing in the clinical molecular diagnosis of 319 Chinese families with inherited retinal dystrophy and comparison study. Genes. 2018;9:360.
[PMID: 30029497]
Liu X, Tao T, Zhao L, Li G, Yang L. Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non���syndromic inherited retinal dystrophies. Clin Exp Ophthalmol. 2021;49:46���59.
[PMID: 33090715]
Ma DJ, Lee H-S, Kim K, Choi S, Jang I, Cho S-H, et al. Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration. BMC Med Genom. 2021;14:74.
[DOI: 10.1186/s12920-021-00874-6]
Moon D, Park HW, Surl D, Won D, Lee S-T, Shin S, et al. Precision medicine through next-generation sequencing in inherited eye diseases in a Korean Cohort. Genes. 2022;13:27.
[DOI: 10.3390/genes13010027]
Tajiguli A, Xu M, Fu Q, Yiming R, Wang K, Li Y, et al. Next-generation sequencing-based molecular diagnosis of 12 inherited retinal disease probands of Uyghur ethnicity. Sci Rep. 2016; 6.; https://doi.org/10.1038/srep21384 .
Maeda A, Yoshida A, Kawai K, Arai Y, Akiba R, Inaba A, et al. Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population. Jpn J Ophthalmol. 2018;62:451���7.
[PMID: 29785639]
Lee BJH, Tham Y-C, Tan T-E, Bylstra Y, Lim WK, Jain K, et al. Characterizing the genotypic spectrum of retinitis pigmentosa in East Asian populations: a systematic review. Ophthalmic Genet. 2023;44:109���18.
[PMID: 36856324]
Liu X, Xiao J, Huang H, Guan L, Zhao K, Xu Q, et al. Molecular genetic testing in clinical diagnostic assessments that demonstrate correlations in patients with autosomal recessive inherited retinal dystrophy. JAMA Ophthalmol. 2015;133:427���36.
[PMID: 25611614]
Durbin R. Efficient haplotype matching and storage using the positional Burrows���Wheeler transform (PBWT). Bioinforma Oxf Engl. 2014;30:1266���72.
[DOI: 10.1093/bioinformatics/btu014]
van der Auwera G, O���Connor BD. Genomics in the cloud: Using docker, GATK, and WDL in terra. O���Reilly Media, Incorporated. 2020 https://books.google.com.sg/books?id=wwiCswEACAAJ .
McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GRS, Thormann A, et al. The ensembl variant effect predictor. Genome Biol. 2016;17:122.
[PMID: 27268795]
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med J Am Coll Med Genet. 2015;17:405���24.
Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: An ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877���85.
[PMID: 27666373]
Sundaram L, Gao H, Padigepati SR, McRae JF, Li Y, Kosmicki JA, et al. Predicting the clinical impact of human mutation with deep neural networks. Nat Genet. 2018;50:1161���70.
[PMID: 30038395]
Jaganathan K, Panagiotopoulou SK, McRae JF, Darbandi SF, Knowles D, Li YI, et al. Predicting splicing from primary sequence with deep learning. Cell. 2019;176:535���548.e24.
[PMID: 30661751]
Plagnol V, Curtis J, Epstein M, Mok KY, Stebbings E, Grigoriadou S, et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics. 2012;28:2747���54.
[PMID: 22942019]
Chan SH, Bylstra Y, Teo JX, Kuan JL, Bertin N, Gonzalez-Porta M, et al. Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nat Commun. 2022;13:6694.
[PMID: 36335097]
Gudmundsson S, Singer-Berk M, Watts NA, Phu W, Goodrich JK, Solomonson M, et al. Variant interpretation using population databases: Lessons from gnomAD. Hum Mutat. 2022;43:1012���30.
[PMID: 34859531]
Martin AR, Williams E, Foulger RE, Leigh S, Daugherty LC, Niblock O, et al. PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019;51:1560���5.
[PMID: 31676867]
R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing: Vienna, Austria. 2024 https://www.R-project.org/ .
Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen W-M. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010;26:2867���73.
[PMID: 20926424]
Gao F-J, Li J-K, Chen H, Hu F-Y, Zhang S-H, Qi Y-H, et al. Genetic and clinical findings in a large cohort of chinese patients with suspected retinitis pigmentosa. Ophthalmology. 2019;126:1549���56.
[PMID: 31054281]
Dan H, Huang X, Xing Y, Shen Y. Application of targeted panel sequencing and whole exome sequencing for 76 Chinese families with retinitis pigmentosa. Mol Genet Genom Med. 2020;8:e1131.
[DOI: 10.1002/mgg3.1131]
Meng XH, Guo H, Xu HW, Li QY, Jin X, Bai Y, et al. Identification of novel CYP4V2 gene mutations in 92 Chinese families with Bietti���s crystalline corneoretinal dystrophy. Mol Vis. 2014;20:1806���14.
[PMID: 25593508]
Su BN, Shen RJ, Liu ZL, Li Y, Jin ZB. Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy. Front Aging Neurosci. 2022; 14. https://www.frontiersin.org/articles/10.3389/fnagi.2022.948279 (accessed 22 Jan2024).
Payne AM, Downes SM, Bessant DAR, Bird AC, Bhattacharya SS. Founder Effect, Seen in the British Population, of the 172 Peripherin/RDS Mutation���and Further Refinement of Genetic Positioning of the Peripherin/RDS Gene. Am J Hum Genet. 1998;62:192���5.
[PMID: 9443872]
Hanany M, Sharon D. Allele frequency analysis of variants reported to cause autosomal dominant inherited retinal diseases question the involvement of 19% of genes and 10% of reported pathogenic variants. J Med Genet. 2019;56:536���42.
[PMID: 30910914]
K��hler S, Gargano M, Matentzoglu N, Carmody LC, Lewis-Smith D, Vasilevsky NA, et al. The Human Phenotype Ontology in 2021. Nucleic Acids Res. 2021;49:D1207���D1217.
[PMID: 33264411]
Falkenberg KD, Braverman NE, Moser AB, Steinberg SJ, Klouwer FCC, Schl��ter A, et al. Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder. Am J Hum Genet. 2017;101:965���76.
[PMID: 29220678]
Shanks ME, Downes SM, Copley RR, Lise S, Broxholme J, Hudspith KA, et al. Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease. Eur J Hum Genet. 2013;21:274���80.
[PMID: 22968130]
Weisschuh N, Mazzola P, Zuleger T, Schaeferhoff K, K��hlewein L, Kort��m F, et al. Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases. J Med Genet. 2023;61:186���95.
Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, et al. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology. 2017;124:1314���31.
[PMID: 28559085]
De Bruijn SE, Fadaie Z, Cremers FPM, Kremer H, Roosing S. The Impact of Modern Technologies on Molecular Diagnostic Success Rates, with a Focus on Inherited Retinal Dystrophy and Hearing Loss. Int J Mol Sci. 2021;22:2943.
[PMID: 33799353]
Kim Y-J, Kim Y-N, Yoon Y-H, Seo E-J, Seo G-H, Keum C, et al. Diverse genetic landscape of suspected retinitis pigmentosa in a large Korean Cohort. Genes. 2021;12:675.
[PMID: 33946315]
Haer-Wigman L, Van Zelst-Stams WA, Pfundt R, Van Den Born LI, Klaver CC, Verheij JB, et al. Diagnostic exome sequencing in 266 Dutch patients with visual impairment. Eur J Hum Genet. 2017;25:591���9.
[PMID: 28224992]
Bylstra Y, Lim WK, Kam S, Tham KW, Wu RR, Teo JX, et al. Family history assessment significantly enhances delivery of precision medicine in the genomics era. Genome Med. 2021;13:3.
[PMID: 33413596]
Botto C, Rucli M, Tekinsoy MD, Pulman J, Sahel J-A, Dalkara D. Early and late stage gene therapy interventions for inherited retinal degenerations. Prog Retin Eye Res. 2022;86:100975.
[PMID: 34058340]
Li S, Xiao X, Yi Z, Sun W, Wang P, Zhang Q. RPE65 mutation frequency and phenotypic variation according to exome sequencing in a tertiary centre for genetic eye diseases in China. Acta Ophthalmol. 2020;98:e181���e190.
[PMID: 31273949]
Mamatha G, Srilekha S, Meenakshi S, Kumaramanickavel G. Screening of the RPE65 gene in the Asian Indian patients with leber congenital amaurosis. Ophthalmic Genet. 2008;29:73���78.
[PMID: 18484312]
Zhong Z, Rong F, Dai Y, Yibulayin A, Zeng L, Liao J, et al. Seven novel variants expand the spectrum of RPE65-related Leber congenital amaurosis in the Chinese population. Mol Vis. 2019;25:204���14.
[PMID: 30996589]
Pierce EA, Aleman TS, Ashimatey B, Kim K, Rashid R, Myers R, et al. Safety and efficacy of EDIT-101 for Treatment of CEP290-associated Retinal Degeneration. Invest Ophthalmol Vis Sci. 2023;64:3785.
Zhu T, Shen Y, Sun Z, Han X, Wei X, Li W, et al. Clinical and molecular features of a chinese cohort with syndromic and nonsyndromic retinal dystrophies related to the CEP290 Gene. Am J Ophthalmol. 2023;248:96���106.
[PMID: 36493848]
