Abstract
High myopia (HM) is a leading cause of visual impairment in the world. To expand the genotypic and phenotypic spectra of HM in the Chinese population, we investigated genetic variations in a cohort of 113 families with nonsyndromic early-onset high myopia from northwestern China by whole-exome sequencing, with focus on 17 known genes. Sixteen potentially pathogenic variants predicted to affect protein function in eight of seventeen causative genes for HM in fifteen (13.3%) families were revealed, including seven novel variants, c.767 + 1G > A in ARR3, c.3214C > A/p.H1072N, and c.2195C > T/p.A732V in ZNF644, c.1270G > T/p.V424L in CPSF1, c.1918G > C/p.G640R and c.2786T > G/p.V929G in XYLT1, c.601G > C/p.E201Q in P4HA2; six rare variants, c.799G > A/p.E267K in NDUFAF7, c.1144C > T/p.R382W in TNFRSF21, c.1100C > T/p.P367L in ZNF644, c.3980C > T/p.S1327L in CPSF1, c.145G > A/p.E49K and c.325G > T/p.G109W in SLC39A5; and three known variants, c.2014A > G/p.S672G and c.3261A > C/p.E1087D in ZNF644, c.605C > T/p.P202L in TNFRSF21. Ten of them were co-segregated with HM. The mean (± SD) examination age of these 15 probands was 14.7 (± 11.61) years. The median spherical equivalent was − 9.50 D (IQ − 8.75 ~ − 12.00) for the right eye and − 11.25 D (IQ − 9.25 ~ − 14.13) for the left eye. The median axial length was 26.67 mm (IQ 25.83 ~ 27.13) for the right eye and 26.25 mm (IQ 25.97 ~ 27.32) for the left eye. These newly identified genetic variations not only broaden the genetic and clinical spectra, but also offer convincing evidence that the genes ARR3, NDUFAF7, TNFRSF21, and ZNF644 contribute to hereditable HM. This work improves further understanding of molecular mechanism of HM.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated or analysed during this study are included in this published article. The raw WES sequencing and blood samples of the 113 patients in the current study are not openly available due to ethical concerns, but are available from the corresponding author on reasonable request.
References
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. https://doi.org/10.1038/nmeth0410-248
Aldahmesh MA, Khan AO, Alkuraya H, Adly N, Anazi S, Al-Saleh AA, Mohamed JY, Hijazi H, Prabakaran S, Tacke M, Al-Khrashi A, Hashem M, Reinheckel T, Assiri A, Alkuraya FS (2013) Mutations in LRPAP1 are associated with severe myopia in humans. Am J Hum Genet 93(2):313–320. https://doi.org/10.1016/j.ajhg.2013.06.002
Anna A, Monika G (2018) Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet 59(3):253–268. https://doi.org/10.1007/s13353-018-0444-7
Bian C, Chen Q, Yu X (2015) The zinc finger proteins ZNF644 and WIZ regulate the G9a/GLP complex for gene repression. Elife 4(4):e05606. https://doi.org/10.7554/eLife.05606
Cai XB, Shen SR, Chen DF, Zhang Q, Jin ZB (2019a) An overview of myopia genetics. Exp Eye Res 188:107778. https://doi.org/10.1016/j.exer.2019.107778
Cai XB, Zheng YH, Chen DF, Zhou FY, Xia LQ, Wen XR, Yuan YM, Han F, Piao SY, Zhuang W, Lu F, Qu J, Yu AY, Jin ZB (2019b) Expanding the phenotypic and genotypic landscape of nonsyndromic high myopia: a cross-sectional study in 731 Chinese patients. Invest Ophthalmol vis Sci 60(12):4052–4062. https://doi.org/10.1167/iovs.19-27921
Feng CY, Huang XQ, Cheng XW, Wu RH, Lu F, Jin ZB (2017) Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients. Sci Rep 7(1):1120. https://doi.org/10.1038/s41598-017-01285-3
Guo H, Tong P, Peng Y, Wang T, Liu Y, Chen J, Li Y, Tian Q, Hu Y, Zheng Y, Xiao L, Xiong W, Pan Q, Hu Z, Xia K (2014a) Homozygous loss-of-function mutation of the LEPREL1 gene causes severe non-syndromic high myopia with early-onset cataract. Clin Genet 86(6):575–579. https://doi.org/10.1111/cge.12309
Guo H, Jin X, Zhu T, Wang T, Tong P, Tian L, Peng Y, Sun L, Wan A, Chen J, Liu Y, Li Y, Tian Q, Xia L, Zhang L, Pan Y, Lu L, Liu Q, Shen L, Li Y, Xiong W, Li J, Tang B, Feng Y, Zhang X, Zhang Z, Pan Q, Hu Z, Xia K (2014b) SLC39A5 mutations interfering with the BMP/TGF-beta pathway in non-syndromic high myopia. J Med Genet 51(8):518–525. https://doi.org/10.1136/jmedgenet-2014-102351
Guo H, Tong P, Liu Y, Xia L, Wang T, Tian Q, Li Y, Hu Y, Zheng Y, Jin X, Li Y, Xiong W, Tang B, Feng Y, Li J, Pan Q, Hu Z, Xia K (2015) Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia. Genet Med 17(4):300–306. https://doi.org/10.1038/gim.2015.28
Haarman AEG, Enthoven CA, Tideman JWL, Tedja MS, Verhoeven VJM, Klaver CCW (2020) The complications of myopia: a review and meta-analysis. Invest Ophthalmol vis Sci 61(4):49. https://doi.org/10.1167/iovs.61.4.49
Holden BA, Fricke TR, Wilson DA, Jong M, Naidoo KS, Sankaridurg P, Wong TY, Naduvilath TJ, Resnikoff S (2016) Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology 123(5):1036–1042. https://doi.org/10.1016/j.ophtha.2016.01.006
Jamieson E, Lester D (2012) The novel human p.I587V variant in the ZNF644 gene is unlikely to be the pathogenic cause of dominantly inherited high myopia in a Chinese patient. Invest Ophthalmol Vis Sci 53(10): 6728. https://doi.org/10.1167/iovs.12-10492.
Jiang D, Li J, Xiao X, Li S, Jia X, Sun W, Guo X, Zhang Q (2015) Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Invest Ophthalmol vis 56(1):339–345. https://doi.org/10.1167/iovs.14-14850
Jin ZB, Gu F, Matsuda H, Yukawa N, Ma X, Nao-i N (2007) Somatic and gonadal mosaicism in X-linked retinitis pigmentosa. Am J Med Genet A 143A(21):2544–2548. https://doi.org/10.1002/ajmg.a.31984
Jin ZB, Wu J, Huang XF, Feng CY, Cai XB, Mao JY, Xiang L, Wu KC, Xiao X, Kloss BA, Li Z, Liu Z, Huang S, Shen M, Cheng FF, Cheng XW, Zheng ZL, Chen X, Zhuang W, Zhang Q, Young TL, Xie T, Lu F, Qu J (2017) Trio-based exome sequencing arrests de novo mutations in early-onset high myopia. Proc Natl Acad Sci USA 114(16):4219–4224. https://doi.org/10.1073/pnas.1615970114
Lee JK, Kim H, Park YM, Kim DH, Lim HT (2017) Mutations in DZIP1 and XYLT1 are associated with nonsyndromic early onset high myopia in the Korean population. Ophthalmic Genet 38(4):395–397. https://doi.org/10.1080/13816810.2016.1232415
Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics 26(5):589–595. https://doi.org/10.1093/bioinformatics/btp698
Li J, Gao B, Guan L, Xiao X, Zhang J, Li S, Jiang H, Jia X, Yang J, Guo X, Yin Y, Wang J, Zhang Q (2015) Unique variants in OPN1LW cause both syndromic and nonsyndromic X-linked high myopia mapped to MYP1. Invest Ophthalmol vis Sci 56(6):4150–4155. https://doi.org/10.1167/iovs.14-16356
Li J, Gao B, Xiao X, Li S, Jia X, Sun W, Guo X, Zhang Q (2016) Exome sequencing identified null mutations in LOXL3 associated with early-onset high myopia. Mol vis 22:161–167
Liu F, Wang J, Xing Y, Li T (2020) Mutation screening of 17 candidate genes in a cohort of 67 probands with early-onset high myopia. Ophthalmic Physiol Opt 40(3):271–280. https://doi.org/10.1111/opo.12683
Lopes MC, Hysi PG, Verhoeven VJ, Macgregor S, Hewitt AW, Montgomery GW, Cumberland P, Vingerling JR, Young TL, van Duijn CM, Oostra B, Uitterlinden AG, Rahi JS, Mackey DA, Klaver CC, Andrew T, Hammond CJ (2013) Identification of a candidate gene for astigmatism. Invest Ophthalmol vis Sci 54(2):1260–1267. https://doi.org/10.1167/iovs.12-10463
Morgan IG, Ohno-Matsui K, Saw SM (2012) Myopia. The Lancet 379(9827):1739–1748. https://doi.org/10.1016/S0140-6736(12)60272-4
Murakami A, Yajima T, Sakuma H, McLaren MJ, Inana G (1993) X-arrestin: a new retinal arrestin mapping to the X chromosome. FEBS Lett 334(2):203–209. https://doi.org/10.1016/0014-5793(93)81712-9
Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31(13):3812–3814. https://doi.org/10.1093/nar/gkg509
Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S (2017) Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 19(10):1105–1117. https://doi.org/10.1038/gim.2017.37
Ouyang J, Sun W, Xiao X, Li S, Jia X, Zhou L, Wang P, Zhang Q (2019) CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection. Hum Mol Genet 28(12):1959–1970. https://doi.org/10.1093/hmg/ddz029
Pan G, Bauer JH, Haridas V, Wang S, Liu D, Yu G, Vincenz C, Aggarwal BB, Ni J, Dixit VM (1998) Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS Lett 431(3):351–356. https://doi.org/10.1016/s0014-5793(98)00791-1
Pan H, Wu S, Wang J, Zhu T, Li T, Wan B, Liu B, Luo Y, Ma X, Sui R, Wang B (2019) TNFRSF21 mutations cause high myopia J Med Genet 56(10): 671–677. https://doi.org/10.1136/jmedgenet-2018-105684.
Rhein VF, Carroll J, Ding S, Fearnley IM, Walker JE (2013) NDUFAF7 methylates arginine 85 in the NDUFS2 subunit of human complex I. J Biol Chem 288(46):33016–33026. https://doi.org/10.1074/jbc.M113.518803
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) 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 17(5):405–424. https://doi.org/10.1038/gim.2015.30
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386. https://doi.org/10.1385/1-59259-192-2:365
Schwarz JM, Rödelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575–576. https://doi.org/10.1038/nmeth0810-575
Shi Y, Li Y, Zhang D, Zhang H, Li Y, Lu F, Liu X, He F, Gong B, Cai L, Li R, Liao S, Ma S, Lin H, Cheng J, Zheng H, Shan Y, Chen B, Hu J, Jin X, Zhao P, Chen Y, Zhang Y, Lin Y, Li X, Fan Y, Yang H, Wang J, Yang Z (2011) Exome sequencing identifies ZNF644 mutations in high myopia. PLoS Genet 7(6):e1002084. https://doi.org/10.1371/journal.pgen.1002084
Széll N, Fehér T, Maróti Z, Kalmár T, Latinovics D, Nagy I, Orosz ZZ, Janáky M, Facskó A, Sohajda Z (2021) Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family. Orphanet J Rare Dis 16(1):45. https://doi.org/10.1186/s13023-021-01673-z
Tran-Viet KN, Powell C, Barathi VA, Klemm T, Maurer-Stroh S, Limviphuvadh V, Soler V, Ho C, Yanovitch T, Schneider G, Li YJ, Nading E, Metlapally R, Saw SM, Goh L, Rozen S, Young TL (2012) Study of a US cohort supports the role of ZNF644 and high-grade myopia susceptibility. Mol vis 18(96–97):937–944. https://doi.org/10.1016/j.ajhg.2013.04.005
Tran-Viet KN, Powell C, Barathi VA, Klemm T, Maurer-Stroh S, Limviphuvadh V, Soler V, Ho C, Yanovitch T, Schneider G, Li YJ, Nading E, Metlapally R, Saw SM, Goh L, Rozen S, Young TL (2013) Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am J Hum Genet 92(5):820–826. https://doi.org/10.1016/j.ajhg.2013.04.005
Wang P, Xiao X, Huang L, Guo X, Zhang Q (2013) Cone-rod dysfunction is a sign of early-onset high myopia. Optom vis Sci off Publ Am Acad Optom 90(11):1327–1330. https://doi.org/10.1097/OPX.0000000000000072
Wang B, Liu Y, Chen S, Wu Y, Lin S, Duan Y, Zheng K, Zhang L, Gu X, Hong W, Shao H, Zeng X, Sun B, Duan S (2017) A novel potentially causative variant of NDUFAF7 revealed by mutation screening in a Chinese family with pathologic myopia. Invest Ophthalmol vis Sci 58(10):4182–4192. https://doi.org/10.1167/iovs.16-20941
Wojciechowski R (2011) Nature and nurture: the complex genetics of myopia and refractive error. Clin Genet 79(4):301–320. https://doi.org/10.1111/j.1399-0004.2010.01592.x
Wong YL, Saw SM (2016) Epidemiology of pathologic myopia in Asia and worldwide. Asia Pac J Ophthalmol (phila) 5(6):394–402. https://doi.org/10.1097/APO.0000000000000234
Wong TY, Ferreira A, Hughes R, Carter G, Mitchell P (2014) Epidemiology and disease burden of pathologic myopia and myopic choroidal neovascularization: an evidence-based systematic review. Am J Ophthalmol 157(1):9–25. https://doi.org/10.1016/j.ajo.2013.08.010
Wu PC, Huang HM, Yu HJ, Fang PC, Chen CT (2016) Epidemiology of myopia. Asia Pac J Ophthalmol (phila) 5(6):386–393. https://doi.org/10.1097/APO.0000000000000236
Xiao X, Li S, Jia X, Guo X, Zhang Q (2016) X-linked heterozygous mutations in ARR3 cause female-limited early onset high myopia. Mol vis 22:1257–1266
Zhang Q (2015) Genetics of refraction and myopia. Prog Mol Biol Transl Sci 134:269–279. https://doi.org/10.1016/bs.pmbts.2015.05.007
Zhang Q (2021) Genetics of pathologic myopia. Pathologic Myopia. https://doi.org/10.1007/978-3-030-74334-5_4
Zhang JY, Zhou B, Sun RY, Ai YL, Cheng K, Li FN, Wang BR, Liu FJ, Jiang ZH, Wang WJ, Zhou D, Chen HZ, Wu Q (2012) Death receptor 6 induces apoptosis not through type I or type II pathways, but via a unique mitochondria-dependent pathway by interacting with Bax protein. J Biol Chem 287(34):29125–29133. https://doi.org/10.1038/s41422-021-00506-9
Zhao F, Wu J, Xue A, Su Y, Wang X, Lu X, Zhou Z, Qu J, Zhou X (2013) Exome sequencing reveals CCDC111 mutation associated with high myopia. Hum Genet 132(8):913–921. https://doi.org/10.1007/s00439-013-1303-6
Zurita Rendón O, Silva Neiva L, Sasarman F, Shoubridge EA (2014) The arginine methyltransferase NDUFAF7 is essential for complex I assembly and early vertebrate embryogenesis. Hum Mol Genet 23(19):5159–5170. https://doi.org/10.1093/hmg/ddu239
Acknowledgements
This study was supported by the National Natural Science Foundation of China (82060182, 82125007), the Ningxia Natural Science Foundation (2021AAC03301) and Ningxia Key R&D program of China (2019BEG03016).
Author information
Authors and Affiliations
Contributions
WZ and ZJ designed the work and revised the manuscript; MY, YQ, BC, LM, ZM, and YL performed the experiments; MY, YQ, and BC analyzed and interpreted data; MY and YM wrote the manuscript. All authors approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interest.
Additional information
Communicated by Shuhua Xu.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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. Mol Genet Genomics 298, 669–682 (2023). https://doi.org/10.1007/s00438-023-02003-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00438-023-02003-7