1932

Abstract

The axial length of the eye is critical for normal visual function by enabling light to precisely focus on the retina. The mean axial length of the adult human eye is 23.5 mm, but the molecular mechanisms regulating ocular axial length remain poorly understood. Underdevelopment can lead to microphthalmia (defined as a small eye with an axial length of less than 19 mm at 1 year of age or less than 21 mm in adulthood) within the first trimester of pregnancy. However, continued overgrowth can lead to axial high myopia (an enlarged eye with an axial length of 26.5 mm or more) at any age. Both conditions show high genetic and phenotypic heterogeneity associated with significant visual morbidity worldwide. More than 90 genes can contribute to microphthalmia, and several hundred genes are associated with myopia, yet diagnostic yields are low. Crucially, the genetic pathways underpinning the specification of eye size are only now being discovered, with evidence suggesting that shared molecular pathways regulate under- or overgrowth of the eye. Improving our mechanistic understanding of axial length determination will help better inform us of genotype–phenotype correlations in both microphthalmia and myopia, dissect gene–environment interactions in myopia, and develop postnatal therapies that may influence overall eye growth.

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2023-08-25
2024-04-15
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Literature Cited

  1. 1.
    Aldahmesh MA, Khan AO, Alkuraya H, Adly N, Anazi S et al. 2013. Mutations in LRPAP1 are associated with severe myopia in humans. Am. J. Hum. Genet. 93:313–20
    [Google Scholar]
  2. 2.
    Almoallem B, Arno G, De Zaeytijd J, Verdin H, Balikova I et al. 2020. The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56. Sci. Rep. 10:1289
    [Google Scholar]
  3. 3.
    Awadalla MS, Burdon KP, Souzeau E, Landers J, Hewitt AW et al. 2014. Mutation in TMEM98 in a large white kindred with autosomal dominant nanophthalmos linked to 17p12-q12. JAMA Ophthalmol. 132:970–77
    [Google Scholar]
  4. 4.
    Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y et al. 1996. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382:225–30
    [Google Scholar]
  5. 5.
    Bhatia S, Bengani H, Fish M, Brown A, Divizia MT et al. 2013. Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. Am. J. Hum. Genet. 93:1126–34
    [Google Scholar]
  6. 6.
    Biesecker LG, Spinner NB. 2013. A genomic view of mosaicism and human disease. Nat. Rev. Genet. 14:307–20
    [Google Scholar]
  7. 7.
    Boucher P, Li W-P, Matz RL, Takayama Y, Auwerx J et al. 2007. LRP1 functions as an atheroprotective integrator of TGFβ and PDGF signals in the vascular wall: implications for Marfan syndrome. PLOS ONE 2:e448
    [Google Scholar]
  8. 8.
    Busby A, Dolk H, Armstrong B. 2005. Eye anomalies: seasonal variation and maternal viral infections. Epidemiology 16:317–22
    [Google Scholar]
  9. 9.
    Cai X-B, Shen S-R, Chen D-F, Zhang Q, Jin Z-B. 2019. An overview of myopia genetics. Exp. Eye Res. 188:107778
    [Google Scholar]
  10. 10.
    Cai X-B, Zheng Y-H, Chen D-F, Zhou F-Y, Xia L-Q et al. 2019. Expanding the phenotypic and genotypic landscape of nonsyndromic high myopia: a cross-sectional study in 731 Chinese patients. Investig. Ophthalmol. Vis. Sci. 60:4052–62
    [Google Scholar]
  11. 11.
    Carricondo PC, Andrade T, Prasov L, Ayres BM, Moroi SE. 2018. Nanophthalmos: a review of the clinical spectrum and genetics. J. Ophthalmol. 2018:2735465
    [Google Scholar]
  12. 12.
    Casey J, Kawaguchi R, Morrissey M, Sun H, McGettigan P et al. 2011. First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: a new dimension to the STRA6 phenotype. Hum. Mutat. 32:1417–26
    [Google Scholar]
  13. 13.
    Chassaing N, Causse A, Vigouroux A, Delahaye A, Alessandri JL et al. 2014. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin. Genet. 86:326–34
    [Google Scholar]
  14. 14.
    Chassaing N, Golzio C, Odent S, Lequeux L, Vigouroux A et al. 2009. Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia. Hum. Mutat. 30:E673–81
    [Google Scholar]
  15. 15.
    Chen S, Kadomatsu K, Kondo M, Toyama Y, Toshimori K et al. 2004. Effects of flanking genes on the phenotypes of mice deficient in basigin/CD147. Biochem. Biophys. Res. Commun. 324:147–53
    [Google Scholar]
  16. 16.
    Chow RL, Lang RA. 2001. Early eye development in vertebrates. Annu. Rev. Cell Dev. Biol. 17:255–96
    [Google Scholar]
  17. 17.
    Collery RF, Volberding PJ, Bostrom JR, Link BA, Besharse JC. 2016. Loss of zebrafish Mfrp causes nanophthalmia, hyperopia, and accumulation of subretinal macrophages. Investig. Ophthalmol. Vis. Sci. 57:6805–14
    [Google Scholar]
  18. 18.
    Coutinho P, Pavlou S, Bhatia S, Chalmers KJ, Kleinjan DA, van Heyningen V. 2011. Discovery and assessment of conserved Pax6 target genes and enhancers. Genome Res. 21:1349–59
    [Google Scholar]
  19. 19.
    Cross SH, McKie L, Hurd TW, Riley S, Wills J et al. 2020. The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification. PLOS Genet. 16:e1008583
    [Google Scholar]
  20. 20.
    Cross SH, McKie L, Keighren M, West K, Thaung C et al. 2019. Missense mutations in the human nanophthalmos gene TMEM98 cause retinal defects in the mouse. Investig. Ophthalmol. Vis. Sci. 60:2875–87
    [Google Scholar]
  21. 21.
    Cvekl A, Ashery-Padan R. 2014. The cellular and molecular mechanisms of vertebrate lens development. Development 141:4432–47
    [Google Scholar]
  22. 22.
    Danno H, Michiue T, Hitachi K, Yukita A, Ishiura S, Asashima M. 2008. Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression. PNAS 105:5408–13
    [Google Scholar]
  23. 23.
    Deming JD, Pak JS, Brown BM, Kim MK, Aung MH et al. 2015. Visual cone arrestin 4 contributes to visual function and cone health. Investig. Ophthalmol. Vis. Sci. 56:5407–16
    [Google Scholar]
  24. 24.
    Deml B, Reis LM, Lemyre E, Clark RD, Kariminejad A, Semina EV. 2016. Novel mutations in PAX6, OTX2 and NDP in anophthalmia, microphthalmia and coloboma. Eur. J. Hum. Genet. 24:535–41
    [Google Scholar]
  25. 25.
    Fan DS, Lam DS, Lam RF, Lau JT, Chong KS et al. 2004. Prevalence, incidence, and progression of myopia of school children in Hong Kong. Investig. Ophthalmol. Vis. Sci. 45:1071–75
    [Google Scholar]
  26. 26.
    Fan Q, Barathi VA, Cheng CY, Zhou X, Meguro A et al. 2012. Genetic variants on chromosome 1q41 influence ocular axial length and high myopia. PLOS Genet. 8:e1002753
    [Google Scholar]
  27. 27.
    Fan Q, Pozarickij A, Tan NY, Guo X, Verhoeven VJ et al. 2020. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error. Commun. Biol. 3:133
    [Google Scholar]
  28. 28.
    Feng C-Y, Huang X-Q, Cheng X-W, Wu R-H, Lu F, Jin Z-B. 2017. Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients. Sci. Rep. 7:1120
    [Google Scholar]
  29. 29.
    Fledelius HC. 1982. Ophthalmic changes from age of 10 to 18 years. A longitudinal study of sequels to low birth weight. IV. Ultrasound oculometry of vitreous and axial length. Acta Ophthalmol. 60:403–11
    [Google Scholar]
  30. 30.
    Flitcroft DI, He M, Jonas JB, Jong M, Naidoo K et al. 2019. IMI – defining and classifying myopia: a proposed set of standards for clinical and epidemiologic studies. Investig. Ophthalmol. Vis. Sci. 60:M20–30
    [Google Scholar]
  31. 31.
    Fogerty J, Besharse JC. 2011. 174delG mutation in mouse MFRP causes photoreceptor degeneration and RPE atrophy. Investig. Ophthalmol. Vis. Sci. 52:7256–66
    [Google Scholar]
  32. 32.
    Foster PJ, Jiang Y. 2014. Epidemiology of myopia. Eye 28:202–8
    [Google Scholar]
  33. 33.
    Furuta Y, Hogan BL. 1998. BMP4 is essential for lens induction in the mouse embryo. Genes Dev. 12:3764–75
    [Google Scholar]
  34. 34.
    Gal A, Rau I, El Matri L, Kreienkamp HJ, Fehr S et al. 2011. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease. Am. J. Hum. Genet. 88:382–90
    [Google Scholar]
  35. 35.
    Gerth-Kahlert C, Williamson K, Ansari M, Rainger JK, Hingst V et al. 2013. Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center. Mol. Genet. Genom. Med. 1:15–31
    [Google Scholar]
  36. 36.
    Gestri G, Bazin-Lopez N, Scholes C, Wilson SW. 2018. Cell behaviors during closure of the choroid fissure in the developing eye. Front. Cell Neurosci. 12:42
    [Google Scholar]
  37. 37.
    Guggenheim JA, Kirov G, Hodson SA. 2000. The heritability of high myopia: a reanalysis of Goldschmidt's data. J. Med. Genet. 37:227–31
    [Google Scholar]
  38. 38.
    Guo H, Jin X, Zhu T, Wang T, Tong P et al. 2014. SLC39A5 mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia. J. Med. Genet. 51:518–25
    [Google Scholar]
  39. 39.
    Guo H, Tong P, Liu Y, Xia L, Wang T et al. 2015. Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia. Genet. Med. 17:300–6
    [Google Scholar]
  40. 40.
    Guo H, Tong P, Peng Y, Wang T, Liu Y et al. 2014. Homozygous loss-of-function mutation of the LEPREL1 gene causes severe non-syndromic high myopia with early-onset cataract. Clin. Genet. 86:575–79
    [Google Scholar]
  41. 41.
    Hammond CJ, Snieder H, Gilbert CE, Spector TD. 2001. Genes and environment in refractive error: the twin eye study. Investig. Ophthalmol. Vis. Sci. 42:1232–36
    [Google Scholar]
  42. 42.
    Harding P, Cunha DL, Moosajee M. 2021. Animal and cellular models of microphthalmia. Ther. Adv. Rare Dis. 2:2633004021997447
    [Google Scholar]
  43. 43.
    Harding P, Gore S, Malka S, Rajkumar J, Oluonye N, Moosajee M. 2022. Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma. Br. J. Ophthalmol. https://doi.org/10.1136/bjo-2022-321991
    [Crossref] [Google Scholar]
  44. 44.
    Harding P, Moosajee M. 2019. The molecular basis of human anophthalmia and microphthalmia. J. Dev. Biol. 7:16
    [Google Scholar]
  45. 45.
    Hendriks M, Verhoeven VJM, Buitendijk GHS, Polling JR, Meester-Smoor MA et al. 2017. Development of refractive errors—what can we learn from inherited retinal dystrophies?. Am. J. Ophthalmol. 182:81–89
    [Google Scholar]
  46. 46.
    Holden BA, Fricke TR, Wilson DA, Jong M, Naidoo KS et al. 2016. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology 123:1036–42
    [Google Scholar]
  47. 47.
    Hornby SJ, Gilbert CE, Rahi J, Sil AK, Xiao Y et al. 2000. Regional variation in blindness in children due to microphthalmos, anophthalmos and coloboma. Ophthalmic Epidemiol. 7:127–38
    [Google Scholar]
  48. 48.
    Hysi PG, Choquet H, Khawaja AP, Wojciechowski R, Tedja MS et al. 2020. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia. Nat. Genet. 52:401–7
    [Google Scholar]
  49. 49.
    Hysi PG, Young TL, Mackey DA, Andrew T, Fernández-Medarde A et al. 2010. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat. Genet. 42:902–5
    [Google Scholar]
  50. 50.
    Jiang D, Li J, Xiao X, Li S, Jia X et al. 2015. Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Investig. Ophthalmol. Vis. Sci. 56:339–45
    [Google Scholar]
  51. 51.
    Jiang Y, Ouyang J, Li X, Wang Y, Zhou L et al. 2021. Novel BMP4 truncations resulted in opposite ocular anomalies: pathologic myopia rather than microphthalmia. Front. Cell Dev. Biol. 9:769636
    [Google Scholar]
  52. 52.
    Jin Z-B, Wu J, Huang X-F, Feng C-Y, Cai X-B et al. 2017. Trio-based exome sequencing arrests de novo mutations in early-onset high myopia. PNAS 114:4219–24
    [Google Scholar]
  53. 53.
    Jobling AI, Nguyen M, Gentle A, McBrien NA. 2004. Isoform-specific changes in scleral transforming growth factor-β expression and the regulation of collagen synthesis during myopia progression. J. Biol. Chem. 279:18121–26
    [Google Scholar]
  54. 54.
    Jobling AI, Wan R, Gentle A, Bui BV, McBrien NA. 2009. Retinal and choroidal TGF-β in the tree shrew model of myopia: isoform expression, activation and effects on function. Exp. Eye Res. 88:458–66
    [Google Scholar]
  55. 55.
    Källén B, Tornqvist K. 2005. The epidemiology of anophthalmia and microphthalmia in Sweden. Eur. J. Epidemiol. 20:345–50
    [Google Scholar]
  56. 56.
    Kamachi Y, Uchikawa M, Tanouchi A, Sekido R, Kondoh H. 2001. Pax6 and SOX2 form a co-DNA-binding partner complex that regulates initiation of lens development. Genes Dev. 15:1272–86
    [Google Scholar]
  57. 57.
    Katoh M. 2001. Molecular cloning and characterization of MFRP, a novel gene encoding a membrane-type Frizzled-related protein. Biochem. Biophys. Res. Commun. 282:116–23
    [Google Scholar]
  58. 58.
    Khan AO. 2008. Posterior microphthalmos versus nanophthalmos. Ophthalmic Genet. 29:189
    [Google Scholar]
  59. 59.
    Khan AO, Aldahmesh MA, Alsharif H, Alkuraya FS. 2015. Recessive mutations in LEPREL1 underlie a recognizable lens subluxation phenotype. Ophthalmic Genet. 36:58–63
    [Google Scholar]
  60. 60.
    Khor CC, Miyake M, Chen LJ, Shi Y, Barathi VA et al. 2013. Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia. Hum. Mol. Genet. 22:5288–94
    [Google Scholar]
  61. 61.
    Kiefer AK, Tung JY, Do CB, Hinds DA, Mountain JL et al. 2013. Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia. PLOS Genet. 9:e1003299
    [Google Scholar]
  62. 62.
    Kim HT, Kim JW. 2012. Compartmentalization of vertebrate optic neuroephithelium: external cues and transcription factors. Mol. Cells 33:317–24
    [Google Scholar]
  63. 63.
    Kleinjan DA, Bancewicz RM, Gautier P, Dahm R, Schonthaler HB et al. 2008. Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence. PLOS Genet. 4:e29
    [Google Scholar]
  64. 64.
    Koli S, Labelle-Dumais C, Zhao Y, Paylakhi S, Nair KS. 2021. Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation. PLOS Genet. 17:e1009458
    [Google Scholar]
  65. 65.
    Lafaut BA, Loeys B, Leroy BP, Spileers W, De Laey JJ, Kestelyn P. 2001. Clinical and electrophysiological findings in autosomal dominant vitreoretinochoroidopathy: report of a new pedigree. Graefe's Arch. . Clin. Exp. Ophthalmol. 239:575–82
    [Google Scholar]
  66. 66.
    Li H, Wang JX, Wang CY, Yu P, Zhou Q et al. 2008. Localization of a novel gene for congenital nonsyndromic simple microphthalmia to chromosome 2q11–14. Hum. Genet. 122:589–93
    [Google Scholar]
  67. 67.
    Li J, Gao B, Guan L, Xiao X, Zhang J et al. 2015. Unique variants in OPN1LW cause both syndromic and nonsyndromic X-linked high myopia mapped to MYP1. Investig. Ophthalmol. Vis. Sci. 56:4150–55
    [Google Scholar]
  68. 68.
    Li J, Zhang Q. 2017. Insight into the molecular genetics of myopia. Mol. Vis. 23:1048–80
    [Google Scholar]
  69. 69.
    Li Y-J, Goh L, Khor CC, Fan Q, Yu M et al. 2011. Genome-wide association studies reveal genetic variants in CTNND2 for high myopia in Singapore Chinese. Ophthalmology 118:368–75
    [Google Scholar]
  70. 70.
    Liao X, Lan C, Liao D, Tian J, Huang X. 2016. Exploration and detection of potential regulatory variants in refractive error GWAS. Sci. Rep. 6:33090
    [Google Scholar]
  71. 71.
    Logan NS, Gilmartin B, Marr JE, Stevenson MR, Ainsworth JR. 2004. Community-based study of the association of high myopia in children with ocular and systemic disease. Optom. Vis. Sci. 81:11–13
    [Google Scholar]
  72. 72.
    Loosli F, Staub W, Finger-Baier KC, Ober EA, Verkade H et al. 2003. Loss of eyes in zebrafish caused by mutation of chokh/rx3. EMBO Rep. 4:894–99
    [Google Scholar]
  73. 73.
    Lotery AJ, Jacobson SG, Fishman GA, Weleber RG, Fulton AB et al. 2001. Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch. Ophthalmol. 119:415–20
    [Google Scholar]
  74. 74.
    Lyhne N, Sjølie AK, Kyvik KO, Green A. 2001. The importance of genes and environment for ocular refraction and its determiners: a population based study among 20–45 year old twins. Br. J. Ophthalmol. 85:1470–76
    [Google Scholar]
  75. 75.
    Marr JE, Halliwell-Ewen J, Fisher B, Soler L, Ainsworth JR. 2001. Associations of high myopia in childhood. Eye 15:70–74
    [Google Scholar]
  76. 76.
    Martinez-Morales JR, Cavodeassi F, Bovolenta P. 2017. Coordinated morphogenetic mechanisms shape the vertebrate eye. Front. Neurosci. 11:721
    [Google Scholar]
  77. 77.
    Martorina M. 1988. Nanophtalmie familiale. J. Fr. Ophtalmol. 11:357–61
    [Google Scholar]
  78. 78.
    Matías-Pérez D, García-Montaño LA, Cruz-Aguilar M, García-Montalvo IA, Nava-Valdéz J et al. 2018. Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and/or anophthalmia by next-generation sequencing. J. Hum. Genet. 63:1169–80
    [Google Scholar]
  79. 79.
    Medina-Martinez O, Amaya-Manzanares F, Liu C, Mendoza M, Shah R et al. 2009. Cell-autonomous requirement for Rx function in the mammalian retina and posterior pituitary. PLOS ONE 4:e4513
    [Google Scholar]
  80. 80.
    Moradian S, Kanani A, Esfandiari H. 2011. Nanophthalmos. J. Ophthalmic Vis. Res. 6:145–46
    [Google Scholar]
  81. 81.
    Mordechai S, Gradstein L, Pasanen A, Ofir R, El Amour K et al. 2011. High myopia caused by a mutation in LEPREL1, encoding prolyl 3-hydroxylase 2. Am. J. Hum. Genet. 89:438–45
    [Google Scholar]
  82. 82.
    Mukhopadhyay R, Sergouniotis PI, Mackay DS, Day AC, Wright G et al. 2010. A detailed phenotypic assessment of individuals affected by MFRP-related oculopathy. Mol. Vis. 16:540–48
    [Google Scholar]
  83. 83.
    Mutti DO, Zadnik K, Adams AJ. 1996. Myopia: The nature versus nurture debate goes on. Investig. Ophthalmol. Vis. Sci. 37:952–57
    [Google Scholar]
  84. 84.
    Myllyharju J. 2008. Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets. Ann. Med. 40:402–17
    [Google Scholar]
  85. 85.
    Nair KS, Hmani-Aifa M, Ali Z, Kearney AL, Ben Salem S et al. 2011. Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. Nat. Genet. 43:579–84
    [Google Scholar]
  86. 86.
    Neri A, Leaci R, Zenteno JC, Casubolo C, Delfini E, Macaluso C. 2012. Membrane frizzled-related protein gene–related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature. Mol. Vis. 18:2623–32
    [Google Scholar]
  87. 87.
    Ohno-Matsui K, Wu P-C, Yamashiro K, Vutipongsatorn K, Fang Y et al. 2021. IMI pathologic myopia. Investig. Ophthalmol. Vis. Sci. 62:5 Erratum 2021. Investig. Ophthalmol. Vis. Sci. 62:17
    [Google Scholar]
  88. 88.
    Orosz O, Rajta I, Vajas A, Takács L, Csutak A et al. 2017. Myopia and late-onset progressive cone dystrophy associate to LVAVA/MVAVA exon 3 interchange haplotypes of opsin genes on chromosome X. Investig. Ophthalmol. Vis. Sci. 58:1834–42
    [Google Scholar]
  89. 89.
    Orr A, Dubé MP, Zenteno JC, Jiang H, Asselin G et al. 2011. Mutations in a novel serine protease PRSS56 in families with nanophthalmos. Mol. Vis. 17:1850–61
    [Google Scholar]
  90. 90.
    Othman MI, Sullivan SA, Skuta GL, Cockrell DA, Stringham HM et al. 1998. Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11. Am. J. Hum. Genet. 63:1411–18
    [Google Scholar]
  91. 91.
    Pardue MT, Stone RA, Iuvone PM. 2013. Investigating mechanisms of myopia in mice. Exp. Eye Res. 114:96–105
    [Google Scholar]
  92. 92.
    Patel A, Hayward JD, Tailor V, Nyanhete R, Ahlfors H et al. 2019. The Oculome panel test: next-generation sequencing to diagnose a diverse range of genetic developmental eye disorders. Ophthalmology 126:888–907
    [Google Scholar]
  93. 93.
    Paun CC, Pijl BJ, Siemiatkowska AM, Collin RW, Cremers FP et al. 2012. A novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen. Mol. Vis. 18:2447–53
    [Google Scholar]
  94. 94.
    Pickrell JK, Berisa T, Liu JZ, Ségurel L, Tung JY, Hinds DA. 2016. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48:709–17
    [Google Scholar]
  95. 95.
    Piekutowska-Abramczuk D, Kocyła-Karczmarewicz B, Małkowska M, Łuczak S, Iwanicka-Pronicka K et al. 2015. No evidence for association of SCO2 heterozygosity with high-grade myopia or other diseases with possible mitochondrial dysfunction. JIMD Rep. 27:63–68
    [Google Scholar]
  96. 96.
    Plaisancie J, Calvas P, Chassaing N. 2016. Genetic advances in microphthalmia. J. Pediatr. Genet. 5:184–88
    [Google Scholar]
  97. 97.
    Prasov L, Guan B, Ullah E, Archer SM, Ayres BM et al. 2020. Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort. Sci. Rep. 10:19986
    [Google Scholar]
  98. 98.
    Rada JA, Shelton S, Norton TT. 2006. The sclera and myopia. Exp. Eye Res. 82:185–200
    [Google Scholar]
  99. 99.
    Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA et al. 2005. Heterozygous mutations of OTX2 cause severe ocular malformations. Am. J. Hum. Genet. 76:1008–22
    [Google Scholar]
  100. 100.
    Ragge NK, Subak-Sharpe ID, Collin JR. 2007. A practical guide to the management of anophthalmia and microphthalmia. Eye 21:1290–300
    [Google Scholar]
  101. 101.
    Reis LM, Tyler RC, Schilter KF, Abdul-Rahman O, Innis JW et al. 2011. BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome. Hum. Genet. 130:495–504
    [Google Scholar]
  102. 102.
    Relhan N, Jalali S, Pehre N, Rao HL, Manusani U, Bodduluri L. 2016. High-hyperopia database, part I: clinical characterisation including morphometric (biometric) differentiation of posterior microphthalmos from nanophthalmos. Eye 30:120–26
    [Google Scholar]
  103. 103.
    Richardson R, Sowden J, Gerth-Kahlert C, Moore AT, Moosajee M. 2017. Clinical utility gene card for: non-syndromic microphthalmia including next-generation sequencing-based approaches. Eur. J. Hum. Genet. 25:512
    [Google Scholar]
  104. 104.
    Richardson R, Tracey-White D, Webster A, Moosajee M. 2017. The zebrafish eye—a paradigm for investigating human ocular genetics. Eye 31:68–86
    [Google Scholar]
  105. 105.
    Rymer J, Wildsoet CF. 2005. The role of the retinal pigment epithelium in eye growth regulation and myopia: a review. Vis. Neurosci. 22:251–61
    [Google Scholar]
  106. 106.
    Saw SM, Gazzard G, Shih-Yen EC, Chua WH. 2005. Myopia and associated pathological complications. Ophthalmic Physiol. Opt. 25:381–91
    [Google Scholar]
  107. 107.
    Schilter KF, Reis LM, Schneider A, Bardakjian TM, Abdul-Rahman O et al. 2013. Whole-genome copy number variation analysis in anophthalmia and microphthalmia. Clin. Genet. 84:473–81
    [Google Scholar]
  108. 108.
    Schilter KF, Schneider A, Bardakjian T, Soucy JF, Tyler RC et al. 2011. OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype. Clin. Genet. 79:158–68
    [Google Scholar]
  109. 109.
    Sellheyer K, Spitznas M. 1988. Development of the human sclera. Graefe's Arch. Clin. Exp. Ophthalmol. 226:89–100
    [Google Scholar]
  110. 110.
    Serjanov D, Bachay G, Hunter DD, Brunken WJ. 2018. Laminin β2 chain regulates retinal progenitor cell mitotic spindle orientation via dystroglycan. J. Neurosci. 38:5996–6010
    [Google Scholar]
  111. 111.
    Shah SP, Taylor AE, Sowden JC, Ragge N, Russell-Eggitt I et al. 2012. Anophthalmos, microphthalmos, and coloboma in the United Kingdom: clinical features, results of investigations, and early management. Ophthalmology 119:362–68
    [Google Scholar]
  112. 112.
    Shaham O, Menuchin Y, Farhy C, Ashery-Padan R. 2012. Pax6: a multi-level regulator of ocular development. Prog. Retin. Eye Res. 31:351–76
    [Google Scholar]
  113. 113.
    Shi Y, Gong B, Chen L, Zuo X, Liu X et al. 2013. A genome-wide meta-analysis identifies two novel loci associated with high myopia in the Han Chinese population. Hum. Mol. Genet. 22:2325–33
    [Google Scholar]
  114. 114.
    Shi Y, Li Y, Zhang D, Zhang H, Li Y et al. 2011. Exome sequencing identifies ZNF644 mutations in high myopia. PLOS Genet. 7:e1002084
    [Google Scholar]
  115. 115.
    Siggs OM, Awadalla MS, Souzeau E, Staffieri SE, Kearns LS et al. 2020. The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort. Clin. Genet. 97:764–69
    [Google Scholar]
  116. 116.
    Siggs OM, Souzeau E, Breen J, Qassim A, Zhou T et al. 2019. Autosomal dominant nanophthalmos and high hyperopia associated with a C-terminal frameshift variant in MYRF. Mol. Vis. 25:527–34
    [Google Scholar]
  117. 117.
    Sinn R, Wittbrodt J. 2013. An eye on eye development. Mech. Dev. 130:347–58
    [Google Scholar]
  118. 118.
    Sivak JG. 2008. The role of the lens in refractive development of the eye: animal models of ametropia. Exp. Eye Res. 87:3–8
    [Google Scholar]
  119. 119.
    Slavotinek A. 2019. Genetics of anophthalmia and microphthalmia. Part 2: syndromes associated with anophthalmia–microphthalmia. Hum. Genet. 138:831–46
    [Google Scholar]
  120. 120.
    Soundararajan R, Won J, Stearns TM, Charette JR, Hicks WL et al. 2014. Gene profiling of postnatal Mfrprd6 mutant eyes reveals differential accumulation of Prss56, visual cycle and phototransduction mRNAs. PLOS ONE 9:e110299
    [Google Scholar]
  121. 121.
    Srour M, Chitayat D, Caron V, Chassaing N, Bitoun P et al. 2013. Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia. Am. J. Hum. Genet. 93:765–72
    [Google Scholar]
  122. 122.
    Stone RA, Pardue MT, Iuvone PM, Khurana TS. 2013. Pharmacology of myopia and potential role for intrinsic retinal circadian rhythms. Exp. Eye Res. 114:35–47
    [Google Scholar]
  123. 123.
    Sundin OH, Dharmaraj S, Bhutto IA, Hasegawa T, McLeod DS et al. 2008. Developmental basis of nanophthalmos: MFRP is required for both prenatal ocular growth and postnatal emmetropization. Ophthalmic Genet. 29:1–9
    [Google Scholar]
  124. 124.
    Tajima T, Ishizu K, Nakamura A. 2013. Molecular and clinical findings in patients with LHX4 and OTX2 mutations. Clin. Pediatr. Endocrinol. 22:15–23
    [Google Scholar]
  125. 125.
    Tedja MS, Wojciechowski R, Hysi PG, Eriksson N, Furlotte NA et al. 2018. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. Nat. Genet. 50:834–48
    [Google Scholar]
  126. 126.
    Tideman JWL, Pärssinen O, Haarman AEG, Khawaja AP, Wedenoja J et al. 2021. Evaluation of shared genetic susceptibility to high and low myopia and hyperopia. JAMA Ophthalmol. 139:601–9
    [Google Scholar]
  127. 127.
    Tideman JWL, Polling JR, Jaddoe VWV, Vingerling JR, Klaver CCW. 2019. Environmental risk factors can reduce axial length elongation and myopia incidence in 6- to 9-year-old children. Ophthalmology 126:127–36
    [Google Scholar]
  128. 128.
    Tran-Viet K-N, Germain ES, Soler V, Powell C, Lim S-H et al. 2012. Study of a US cohort supports the role of ZNF644 and high-grade myopia susceptibility. Mol. Vis. 18:937
    [Google Scholar]
  129. 129.
    Tran-Viet K-N, Powell C, Barathi VA, Klemm T, Maurer-Stroh S et al. 2013. Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am. J. Hum. Genet. 92:820–26
    [Google Scholar]
  130. 130.
    Velez G, Tsang SH, Tsai YT, Hsu CW, Gore A et al. 2017. Gene therapy restores Mfrp and corrects axial eye length. Sci. Rep. 7:16151
    [Google Scholar]
  131. 131.
    Verhoeven VJ, Hysi PG, Wojciechowski R, Fan Q, Guggenheim JA et al. 2013. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat. Genet. 45:314–18
    [Google Scholar]
  132. 132.
    Verma AS, Fitzpatrick DR. 2007. Anophthalmia and microphthalmia. Orphanet J. Rare Dis. 2:47
    [Google Scholar]
  133. 133.
    Wang Y-M, Lu S-Y, Zhang X-J, Chen L-J, Pang C-P, Yam JC. 2022. Myopia genetics and heredity. Children 9:382
    [Google Scholar]
  134. 134.
    Wasmann RA, Wassink-Ruiter JS, Sundin OH, Morales E, Verheij JB, Pott JW. 2014. Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds. Acta Ophthalmol. 92:276–81
    [Google Scholar]
  135. 135.
    Williams KM, Bertelsen G, Cumberland P, Wolfram C, Verhoeven VJ et al. 2015. Increasing prevalence of myopia in Europe and the impact of education. Ophthalmology 122:1489–97
    [Google Scholar]
  136. 136.
    Williamson KA, FitzPatrick DR. 2014. The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur. J. Med. Genet. 57:369–80
    [Google Scholar]
  137. 137.
    Williamson KA, Hall HN, Owen LJ, Livesey BJ, Hanson IM et al. 2020. Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction. Genet. Med. 22:598–609
    [Google Scholar]
  138. 138.
    Wojciechowski R, Congdon N, Bowie H, Munoz B, Gilbert D, West SK. 2005. Heritability of refractive error and familial aggregation of myopia in an elderly American population. Investig. Ophthalmol. Vis. Sci. 46:1588–92
    [Google Scholar]
  139. 139.
    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. 157:9–25.e12
    [Google Scholar]
  140. 140.
    Wu W, Dawson DG, Sugar A, Elner SG, Meyer KA et al. 2004. Cataract surgery in patients with nanophthalmos: results and complications. J. Cataract Refract. Surg. 30:584–90
    [Google Scholar]
  141. 141.
    Wyatt A, Bakrania P, Bunyan DJ, Osborne RJ, Crolla JA et al. 2008. Novel heterozygous OTX2 mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma. Hum. Mutat. 29:E278–83
    [Google Scholar]
  142. 142.
    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
    [Google Scholar]
  143. 143.
    Xiong S, Sankaridurg P, Naduvilath T, Zang J, Zou H et al. 2017. Time spent in outdoor activities in relation to myopia prevention and control: a meta-analysis and systematic review. Acta Ophthalmol. 95:551–66
    [Google Scholar]
  144. 144.
    Yalvac IS, Satana B, Ozkan G, Eksioglu U, Duman S. 2008. Management of glaucoma in patients with nanophthalmos. Eye 22:838–43
    [Google Scholar]
  145. 145.
    Yamani A, Wood I, Sugino I, Wanner M, Zarbin MA. 1999. Abnormal collagen fibrils in nanophthalmos: a clinical and histologic study. Am. J. Ophthalmol. 127:106–8
    [Google Scholar]
  146. 146.
    Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B et al. 2004. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Investig. Ophthalmol. Vis. Sci. 45:3683–89
    [Google Scholar]
  147. 147.
    Young TL, Metlapally R, Shay AE. 2007. Complex trait genetics of refractive error. Arch. Ophthalmol. 125:38–48
    [Google Scholar]
  148. 148.
    Zagozewski JL, Zhang Q, Eisenstat DD. 2014. Genetic regulation of vertebrate eye development. Clin. Genet. 86:453–60
    [Google Scholar]
  149. 149.
    Zenteno JC, Buentello-Volante B, Ayala-Ramirez R, Villanueva-Mendoza C. 2011. Homozygosity mapping identifies the Crumbs homologue 1 (Crb1) gene as responsible for a recessive syndrome of retinitis pigmentosa and nanophthalmos. Am. J. Med. Genet. A 155A:1001–6
    [Google Scholar]
  150. 150.
    Zenteno JC, Buentello-Volante B, Quiroz-González MA, Quiroz-Reyes MA. 2009. Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex. Mol. Vis. 15:1794–98
    [Google Scholar]
  151. 151.
    Zhao F, Wu J, Xue A, Su Y, Wang X et al. 2013. Exome sequencing reveals CCDC111 mutation associated with high myopia. Hum. Genet. 132:913–21
    [Google Scholar]
  152. 152.
    Zuber ME, Gestri G, Viczian AS, Barsacchi G, Harris WA. 2003. Specification of the vertebrate eye by a network of eye field transcription factors. Development 130:5155–67
    [Google Scholar]
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