Analysis of genetic variations and clinical phenotypes in patients with early-onset high myopia associated with hereditary eye diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Wenjing ^1,2 , Qi Xiaolong ² , Shi Baoyu ² , Cui Qianwei ^1,2 , Wang Zhenglai ^1,2 , Li Rui ¹ , Liu Keyan ¹ , Zhang Shaochi ² ,  Zhuang Wenjuan ^1,2

1. The Third Clinical School of Medicine, Ningxia Medical University, Yinchuan 750004, China;
2. Department of Ophthalmology, Ningxia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, China;

Corresponding author：

Zhuang Wenjuan, Email: zh_wenj@163.com

Keywords：

Early-onset high myopia; Inherited retinal diseases; Gene mutation; Congenital Stationary Night Blindness; Stickler syndrome; Familial exudative vitreoretinopathy; Retinitis pigmentosa

DOI：

10.3760/cma.j.cn511434-20241219-00497

Video：

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Objective To investigate and analyze the relationship between genotype and phenotype in patients with early-onset high myopia (eoHM) associated with hereditary eye diseases. Methods A family-based study was conducted among 30 families diagnosed with eoHM at Department of Ophthalmology of People's Hospital of Ningxia Hui Autonomous Region from January 2022 to June 2023. Seven families (23.3%, 7/30), all probands, and their 14 parents were included. These seven families were unrelated. Detailed patient and family histories were collected. All participants underwent comprehensive ophthalmic examinations, including best-corrected visual acuity, color vision testing, fundus color photography, optical coherence tomography, fluorescein fundus angiography, and fundus autofluorescence imaging. Full-field electroretinography was performed in three cases. Peripheral venous blood samples were collected from patients and their parents for whole-genome DNA extraction and whole-exome sequencing. Potential pathogenic variants were identified, and their pathogenicity was analyzed and confirmed by Sanger sequencing. The pathogenicity of newly discovered gene variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Literature on previously reported eoHM associated with hereditary eye diseases was reviewed to analyze the relationship between variant genes and clinical phenotypes. Results Among the seven families, three exhibited X-linked inheritance, two showed autosomal recessive inheritance, and two demonstrated autosomal dominant inheritance. All the patients were male. Among the seven patients, one case each was identified with congenital stationary night blindness (CSNB), Bornholm eye disease, X-linked retinitis pigmentosa (RP), cone-rod dystrophy, Knobloch syndrome, familial exudative vitreoretinopathy (FEVR), and Stickler syndrome. Genetic testing revealed nine gene variants highly correlated with the observed phenotypes. The genetic testing results revealed that all patients were found to carry nine gene variants highly associated with the phenotype, including: a hemizygous missense variant NYX c.647A>T (p.N216I) (M1), an OPN1LW LIAVA haplotype variant (M2), a hemizygous frameshift variant RPGR c.3096_3097del (p.E1033RfsTer45) (M3), compound heterozygous variants TTLL5 c.1588_1589del (p.L531EfsTer24) and c.850G>C (p.D284H) (M4, M5), compound heterozygous variants COL18A1 c.2118dup (p.G707RfsTer23) and c.3523_3524del (p.L1175VfsTer72) (M6, M7), a heterozygous missense mutation FZD4 c.1499C>T (p.T500I) (M8), and a heterozygous frameshift variant COL11A2 c.966dup (p.T323HfsTer19) (M9). Among them, M2, M4, M5, M8 and M9 were newly discovered mutation sites, and M1, M3, M6 and M7 were known mutation sites. According to the classification standards and guidelines of genetic variation issued by ACMG, M2, M3, M4, M6, M7, and M9 were judged to be pathogenic variants, while M1, M5, and M8 were of unknown clinical significance. Through literature review, it was found that eoHM was more common among the clinical phenotypes of 4 types of hereditary retinal diseases, including CSNB, Stickler syndrome, FEVR and RP. Conclusion eoHM is intricately associated with inherited eye diseases and may serve as the earliest indicator of such conditions.

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24.	Sharon D, Sandberg MA, Rabe VW, et al. RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa[J]. Am J Hum Genet, 2003, 73(5): 1131-1146. DOI: 10.1086/379379.
25.	Talib M, van Schooneveld MJ, Van Cauwenbergh C, et al. The spectrum of structural and functional abnormalities in female carriers of pathogenic variants in the RPGR gene[J]. Invest Ophthalmol Vis Sci, 2018, 59(10): 4123-4133. DOI: 10.1167/iovs.17-23453.
26.	Wawrocka A, Skorczyk-Werner A, Wicher K, et al. Novel variants identified with next-generation sequencing in Polish patients with cone-rod dystrophy[J]. Mol Vis, 2018, 24: 326-339.
27.	Sergouniotis PI, Chakarova C, Murphy C, et al. Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy[J]. Am J Hum Genet, 2014, 94(5): 760-769. DOI: 10.1016/j.ajhg.2014.04.003.
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29.	Kolawole OU, Gregory-Evans CY, Bikoo R, et al. Novel pathogenic variants in Tubulin Tyrosine Like 5 (TTLL5) associated with cone-dominant retinal dystrophies and an abnormal optical coherence tomography phenotype[J]. Mol Vis, 2023, 29: 329-337.
30.	Khan AO, Aldahmesh MA, Mohamed JY, et al. The distinct ophthalmic phenotype of Knobloch syndrome in children[J]. Br J Ophthalmol, 2012, 96(6): 890-895. DOI: 10.1136/bjophthalmol-2011-301396.
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1. Széll N, Fehér T, Maróti Z, et al. Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family[J/OL]. Orphanet J Rare Dis, 2021, 16(1): 45[2021-01-22]. https://pmc.ncbi.nlm.nih.gov/articles/PMC7825233/. DOI: 10.1186/s13023-021-01673-z.
2. Ye M, Ma Y, Qin YX, et al. Mutational investigation of 17 causative genes in a cohort of 113 families with nonsyndromic early-onset high myopia in northwestern China[J]. Mol Genet Genomics, 2023, 298(3): 669-682. DOI: 10.1007/s00438-023-02003-7.
3. Zhou L, Xiao X, Li S, et al. Frequent mutations of RetNet genes in eoHM: further confirmation in 325 probands and comparison with late-onset high myopia based on exome sequencing[J]. Exp Eye Res, 2018, 171: 76-91. DOI: 10.1016/j.exer.2018.02.007.
4. Yang E, Yu J, Liu X, et al. Familial whole exome sequencing study of 30 families with early-onset high myopia[J]. Invest Ophthalmol Vis Sci, 2023, 64(5): 1-8. DOI: 10.1167/iovs.65.2.40.
5. ……//[M]. 盛迅伦, 庄文娟. 遗传性眼病的基础与临床. 北京: 人民卫生出版社, 2019: …….Sheng XL, Zhuang WJ. The basis and clinic of hereditary eye diseases [M]. Beijing: People's Medical Publishing House, 2019.
6. Snead MP, Richards AJ, McNinch AM, et al. Stickler syndrome-lessons from a national cohort[J]. Eye (Lond), 2022, 36(10): 1966-1972. DOI: 10.1038/s41433-021-01776-8.
7. Holmquist D, Epstein D, Olsson M, et al. Visual and ocular findings in a family with X-linked cone dysfunction and protanopia[J]. Ophthalmic Genet, 2021, 42(5): 570-576. DOI: 10.1080/13816810.2021.1938139.
8. Arepalli S, Debenedictis MM, Yuan A, et al. Severe retinal complications in Knobloch syndrome three siblings without clinically apparent occipital defects and a review of the literature[J]. Ophthalmic Genet, 2022, 6: 1-9. DOI: 10.1080/13816810.2022.2028297.
9. Zeitz C, Labs S, Lorenz B, et al. Genotyping microarray for CSNB-associated genes[J]. Invest Ophthalmol Vis Sci, 2009, 50(12): 5919-5926. DOI: 10.1167/iovs.09-3548.
10. Yang Z, Peachey NS, Moshfeghi DM, et al. Mutations in the RPGR gene cause X-linked cone dystrophy[J]. Hum Mol Genet, 2002, 11(5): 605-611. DOI: 10.1093/hmg/11.5.605.
11. Yang J, Zhou L, Ouyang J, et al. Genotype-phenotype analysis of RPGR variations: reporting of 62 Chinese families and a literature review[J/OL]. Front Genet, 2021, 12: 600210[2021-06-23]. https://pubmed.ncbi.nlm.nih.gov/34745198/. DOI: 10.3389/fgene.2021.600210.
12. Aldahmesh MA, Khan AO, Mohamed JY, et al. No evidence for locus heterogeneity in Knobloch syndrome[J]. J Med Genet, 2013, 50(8): 565-566. DOI: 10.1136/jmedgenet-2013-101755.
13. Gonzalez-Iglesias E, Lopez-Vazquez A, Noval S, et al. Next-generation sequencing screening of 43 families with non-syndromic early-onset high myopia: a clinical and genetic study[J]. Int J Mol Sci, 2022, 23(8): 1-29. DOI: 10.3390/ijms23084233.
14. Sanchez-Cazorla E, Gonzalez-Atienza C, Lopez-Vazquez A, et al. Whole-exome sequencing of 21 families: candidate genes for early-onset high myopia[J/OL]. Int J Mol Sci, 2023, 24(21): 15676[2023-10-27]. https://pubmed.ncbi.nlm.nih.gov/37958660/. DOI: 10.3390/ijms242115676.
15. Sun W, Huang L, Xu Y, et al. Exome sequencing on 298 probands with early-onset high myopia: approximately one-furth show potential pathogenic mutations in RetNet henes[J]. Invest Ophthalmol Vis Sci, 2015, 56(13): 8365-8372. DOI: 10.1167/iovs.15-17555.
16. Huang L, Lai Y, Sun L, et al. High myopia is common in patients with X-linked retinopathies: myopic maculopathy analysis[J]. Retina, 2024, 44(1): 117-126. DOI: 10.1097/IAE.0000000000003934.
17. De Silva SR, Arno G, Robson AG, et al. The X-linked retinopathies: physiological insights, pathogenic mechanisms, phenotypic features and novel therapies[J/OL]. Prog Retin Eye Res, 2021, 82: 100898[2020-08-26]. https://pubmed.ncbi.nlm.nih.gov/32860923/. DOI: 10.1016/j.preteyeres.2020.100898.
18. Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms[J]. Prog Retin Eye Res, 2015, 45: 58-110. DOI: 10.1016/j.preteyeres.2014.09.001.
19. Katta M, de Guimaraes T, Fujinami-Yokokawa Y, et al. Congenital stationary night blindness: structure, function and genotype-phenotype correlations in a cohort of 122 patients[J]. Ophthalmol Retina, 2024, 8(9): 932-941. DOI: 10.1016/j.oret.2024.03.017.
20. 徐敏, 杜伟. 基因新致病突变引起X连锁隐性遗传先天性静止性夜盲1例[J]. 中华实验眼科杂志, 2022, 40(12): 1206-1207. DOI: 10.3760/cma.j.cn115989-20190907-00387.Xu M, Du W. A novel NYX mutation causes X-linked recessive congenital stationary night blindness: a case report[J]. Chin J Exp Ophthalmol, 2022, 40(12): 1206-1207. DOI: 10.3760/cma.j.cn115989-20190907-00387.
21. 但汉东, 宋秀胜, 李家璋. Schubert-Bornschein型先天性静止性夜盲致病的分子机制[J]. 中国实用眼科杂志, 2016, 34(5): 407-410. DOI: 10.3760/cma.j.issn.1006-4443.2016.05.002.Dan HD, Song XS, Li JZ. Molecular mechanisms underlying congenital stationary night blindness of the schbert-bornschein type[J]. Chin J of Prac Ophthalmol, 2016, 34(5): 407-410. DOI: 10.3760/cma.j.issn.1006-4443.2016.05.002.
22. Neitz M, Wagner-Schuman M, Rowlan JS, et al. Insight from opn1lw gene haplotypes into the cause and prevention of myopia[J]. Genes (Basel), 2022, 13(6): 942. DOI: 10.3390/genes13060942.
23. Haim M, Fledelius HC, Skarsholm. X-linked myopia in Danish family[J]. Acta Ophthalmol (Copenh), 1988, 66(4): 450-456. DOI: 10.1111/j.1755-3768.1988.tb04039.x.
24. Sharon D, Sandberg MA, Rabe VW, et al. RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa[J]. Am J Hum Genet, 2003, 73(5): 1131-1146. DOI: 10.1086/379379.
25. Talib M, van Schooneveld MJ, Van Cauwenbergh C, et al. The spectrum of structural and functional abnormalities in female carriers of pathogenic variants in the RPGR gene[J]. Invest Ophthalmol Vis Sci, 2018, 59(10): 4123-4133. DOI: 10.1167/iovs.17-23453.
26. Wawrocka A, Skorczyk-Werner A, Wicher K, et al. Novel variants identified with next-generation sequencing in Polish patients with cone-rod dystrophy[J]. Mol Vis, 2018, 24: 326-339.
27. Sergouniotis PI, Chakarova C, Murphy C, et al. Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy[J]. Am J Hum Genet, 2014, 94(5): 760-769. DOI: 10.1016/j.ajhg.2014.04.003.
28. Mahalingan KK, Keith KE, Strickland M, et al. Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes[J]. Nat Struct Mol Biol, 2020, 27(9): 802-813. DOI: 10.1038/s41594-020-0462-0.
29. Kolawole OU, Gregory-Evans CY, Bikoo R, et al. Novel pathogenic variants in Tubulin Tyrosine Like 5 (TTLL5) associated with cone-dominant retinal dystrophies and an abnormal optical coherence tomography phenotype[J]. Mol Vis, 2023, 29: 329-337.
30. Khan AO, Aldahmesh MA, Mohamed JY, et al. The distinct ophthalmic phenotype of Knobloch syndrome in children[J]. Br J Ophthalmol, 2012, 96(6): 890-895. DOI: 10.1136/bjophthalmol-2011-301396.
31. Hull S, Arno G, Ku CA, et al. Molecular and clinical findings in patients with knobloch syndrome[J]. JAMA Ophthalmol, 2016, 134(7): 753-762. DOI: 10.1001/jamaophthalmol.2016.1073.
32. Zhang LS, Li HB, Zeng J, et al. Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree[J]. Int J Ophthalmol, 2018, 11(6): 918-922. DOI: 10.18240/ijo.2018.06.04.
33. Li S, Wang Y, Sun L, et al. Knobloch syndrome associated with novel COL18A1 variants in chinese population[J/OL]. Genes (Basel), 2021, 12(10): 1512[2021-09-26]. https://pubmed.ncbi.nlm.nih.gov/34680907/. DOI: 10.3390/genes12101512.
34. 陈春丽, 李筱荣. 家族性渗出性玻璃体视网膜病变的多样性研究现状[J]. 中华眼底病杂志, 2019, 35(5): 517-521. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.022.Chen CL, Li XR. Research status of diversity of familial exudative vitreoretinopathy[J]. Chin J Ocul Fundus Dis, 2019, 35(5): 517-521. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.022.
35. Cicerone AP, Dailey W, Sun M, et al. A survey of multigenic protein-altering variant frequency in familial exudative vitreo-retinopathy (FEVR) patients by targeted sequencing of seven FEVR-linked genes[J]. Genes (Basel), 2022, 13(3): 495. DOI: 10.3390/genes13030495.
36. Wang S, Zhang X, Hu Y, et al. Clinical and genetical features of probands and affected family members with familial exudative vitreoretinopathy in a large Chinese cohort[J]. Br J Ophthalmol, 2021, 105(1): 83-86. DOI: 10.1136/bjophthalmol-2019-315598.
37. 杨依柳, 陆方. 家族性渗出性玻璃体视网膜病变的致病基因与相关信号通路研究进展[J]. 中华眼底病杂志, 2023, 39(7): 594-599. DOI: 10.3760/cma.j.cn511434-20221102-00572.Yang YL, Lu F. Research progresses on pathogenic genes and related signal pathways of familial exudative vitreoretinopathy[J]. Chin J Ocul Fundus Dis, 2023, 39(7): 594-599. DOI: 10.3760/cma.j.cn511434-20221102-00572.
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Chinese Journal of Ocular Fundus Diseases

Latest ArticlesAnalysis of genetic variations and clinical phenotypes in patients with early-onset high myopia associated with hereditary eye diseases

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