Reinforce revealing missing heritability in the gene of inherited retinal diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

 Li Yang , Shi Jie , Zhang Xin

Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing 100730, China;

Corresponding author：

Li Yang, Email: yilbio@163.com

Keywords：

Inherited retinal diseases; Missing variants; Deep intron variants; Structure variants; Editorial

DOI：

10.3760/cma.j.cn511434-20230704-00298

Video：

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Inherited retinal diseases (IRD) are a group of genetic disorders with high genetic and clinical heterogeneity. Genetic diagnosis has become one essential method for patients with IRD in their clinical management. So far, about 30% of the patients with IRD cannot get molecular diagnosis (no pathogenic variant detected or only mono-allele variant identified in AR genes) using target or whole exome sequencing. Most missing heritability or variants for these patients were variants located in no-coding regions (deep intron or promoter regions) and structure variants of the known IRD genes. It is more challenge to reveal this kind of missing variants, which need using whole genome sequencing combined with other cellular or molecular assays.

Citation： Li Yang, Shi Jie, Zhang Xin. Reinforce revealing missing heritability in the gene of inherited retinal diseases. Chinese Journal of Ocular Fundus Diseases, 2023, 39(7): 521-524. doi: 10.3760/cma.j.cn511434-20230704-00298 Copy

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12.	Parfitt DA, Lane A, Ramsden CM, et alIdentification and correction of mechanisms underlying inherited blindness in human iPSC-Derived optic cups[J]. Cell Stem Cell2016186769781. DOI:10.1016/j.stem.2016.03.021.
13.	Xue K, MacLaren REAntisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases[J]. Expert Opin Investig Drugs2020291011631170. DOI:10.1080/13543784.2020.1804853.
14.	Leroy BP, Birch DG, Duncan JL, et al. Leber congenital amaurosis due to CEP290 mutations-severe vision impairment with a high unmet medical need: a review[J]. Retina, 2021, 41(5): 898-907. DOI:10.1097/IAE.0000000000003133.
15.	Russell SR, Drack AV, Cideciyan AV, et alIntravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial[J]. Nat Med202228510141021. DOI:10.1038/s41591-022-01755-w.
16.	Eichler EEGenetic variation, comparative genomics, and the diagnosis of disease[J]. N Engl J Med201938116474. DOI: 10.1056/NEJMra1809315.
17.	Maston GA, Evans SK, Green MRTranscriptional regulatory elements in the human genome[J]. Annu Rev Genomics Hum Genet200672959. DOI:10.1146/annurev.genom.7.080505.115623.
18.	Rose AM, Shah AZ, Waseem NH, et alExpression of PRPF31 and TFPT: regulation in health and retinal disease[J]. Hum Mol Genet2012211841264137. DOI:10.1093/hmg/dds242.
19.	Katagiri S, Iwasa M, Hayashi T, et alGenotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy[J]. Sci Rep20188111507. DOI:10.1038/s41598-018-29891-9.
20.	Coppieters F, Todeschini AL, Fujimaki T, et alHidden genetic variation in LCA9-associated congenital blindness explained by 5'UTR mutations and copy-number variations of NMNAT1[J]. Hum Mutat2015361211881196. DOI:10.1002/humu.22899.
21.	Radziwon A, Arno G, K Wheaton D, et alSingle-base substitutions in the CHM promoter as a cause of choroideremia[J]. Hum Mutat2017386704715. DOI:10.1002/humu.23212.

1. Berger W, Kloeckener-Gruissem B, Neidhardt JThe molecular basis of human retinal and vitreoretinal diseases[J]. Prog Retin Eye Res2010295335375. DOI:10.1016/j.preteyeres. 2010.03.004. doi:10.1016/j.preteyeres.2010.03.004.
2. Ellingford JM, Barton S, Bhaskar S, et alWhole genome sequencing increases molecular diagnostic yield compared with current diagnostic testing for inherited retinal disease[J]. Ophthalmology2016123511431150. DOI:10.1016/j.ophtha.2016.01.009.
3. Zampaglione E, Kinde B, Place EM, et alCopy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations[J]. Genet Med202022610791087. DOI:10.1038/s41436-020-0759-8.
4. Di Scipio M, Tavares E, Deshmukh S, et alPhenotype driven analysis of whole genome sequencing identifies deep intronic variants that cause retinal dystrophies by aberrant exonization[J]. Invest Ophthalmol Vis Sci2020611036. DOI:10.1167/iovs.61.10.36.
5. Weisschuh N, Buena-Atienza E, Wissinger B. Splicing mutations in inherited retinal diseases [J/OL]. Prog Retin Eye Res, 2021, 80: 100874[2020-06-15]. https://linkinghub.elsevier.com/retrieve/pii/S1350-9462(20)30046-X. DOI:10.1016/j.preteyeres.2020.100874.
6. Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations[J/OL]. Prog Retin Eye Res, 2020, 79: 100861[2020-04-09]. https://linkinghub.elsevier.com/retrieve/pii/S1350-9462(20)30033-1. DOI:10.1016/j.preteyeres.2020.100861.
7. Tian L, Chen C, Song Y, et alPhenotype-based genetic analysis reveals missing heritability of ABCA4-related retinopathy: deep intronic variants and copy number variations[J]. Invest Ophthalmol Vis Sci20226365. DOI:10.1167/iovs.63.6.5.
8. Zhang X, Xie Y, Xu K, et alcomprehensive genetic analysis unraveled the missing heritability in a chinese cohort with Wolfram syndrome 1: clinical and genetic findings[J]. Invest Ophthalmol Vis Sci202263109. DOI:10.1167/iovs.63.10.9.
9. Richards S, Aziz N, Bale S, et alStandards 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[J]. Genet Med2015175405424. DOI:10.1038/gim.2015.30.
10. Sangermano R, Garanto A, Khan M, et alDeep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides[J]. Genet Med201921817511760. DOI:10.1038/s41436-018-0414-9.
11. Khan M, Arno G, Fakin A, et alDetailed phenotyping and therapeutic strategies for intronic ABCA4 variants in Stargardt disease[J]. Mol Ther Nucleic Acids202021412427. DOI:10.1016/j.omtn.2020.06.007.
12. Parfitt DA, Lane A, Ramsden CM, et alIdentification and correction of mechanisms underlying inherited blindness in human iPSC-Derived optic cups[J]. Cell Stem Cell2016186769781. DOI:10.1016/j.stem.2016.03.021.
13. Xue K, MacLaren REAntisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases[J]. Expert Opin Investig Drugs2020291011631170. DOI:10.1080/13543784.2020.1804853.
14. Leroy BP, Birch DG, Duncan JL, et al. Leber congenital amaurosis due to CEP290 mutations-severe vision impairment with a high unmet medical need: a review[J]. Retina, 2021, 41(5): 898-907. DOI:10.1097/IAE.0000000000003133.
15. Russell SR, Drack AV, Cideciyan AV, et alIntravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial[J]. Nat Med202228510141021. DOI:10.1038/s41591-022-01755-w.
16. Eichler EEGenetic variation, comparative genomics, and the diagnosis of disease[J]. N Engl J Med201938116474. DOI: 10.1056/NEJMra1809315.
17. Maston GA, Evans SK, Green MRTranscriptional regulatory elements in the human genome[J]. Annu Rev Genomics Hum Genet200672959. DOI:10.1146/annurev.genom.7.080505.115623.
18. Rose AM, Shah AZ, Waseem NH, et alExpression of PRPF31 and TFPT: regulation in health and retinal disease[J]. Hum Mol Genet2012211841264137. DOI:10.1093/hmg/dds242.
19. Katagiri S, Iwasa M, Hayashi T, et alGenotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy[J]. Sci Rep20188111507. DOI:10.1038/s41598-018-29891-9.
20. Coppieters F, Todeschini AL, Fujimaki T, et alHidden genetic variation in LCA9-associated congenital blindness explained by 5'UTR mutations and copy-number variations of NMNAT1[J]. Hum Mutat2015361211881196. DOI:10.1002/humu.22899.
21. Radziwon A, Arno G, K Wheaton D, et alSingle-base substitutions in the CHM promoter as a cause of choroideremia[J]. Hum Mutat2017386704715. DOI:10.1002/humu.23212.

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Reinforce revealing missing heritability in the gene of inherited retinal diseases

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