Myopia 2, Autosomal Dominant

Description

Myopia, or nearsightedness, is a refractive error of the eye. Light rays from a distant object are focused in front of the retina and those from a near object are focused in the retina; therefore distant objects are blurry and near objects are clear (summary by Kaiser et al., 2004).

Genetic Heterogeneity of Susceptibility to Myopia

MYP2 maps to chromosome 18p. Other myopia loci include MYP1 (310460) on Xq28; MYP3 (603221) on 12q21-q23; MYP5 (608474) on 17q21-q22; MYP6 (608908), caused by mutation in the SCO2 gene (602474) on 22q13; MYP7 (609256) on 11p13; MYP8 (609257) on 3q26; MYP9 (609258) on 4q12; MYP10 (609259) on 8p23; MYP11 (609994) on 4q22-q27; MYP12 (609995) on 2q37.1; MYP13 (300613) on Xq23-q27; MYP14 (610320) on 1p36; MYP15 (612717) on 10q21.1; MYP16 (612554) on 5p15.33-p15.2; MYP17 (formerly MYP4) (608367) on 7p15; MYP18 (255500) on chromosome 14q22-q24; MYP19 (613969) on 5p15.1-p13.3; MYP20 (614166) on 13q12.12; MYP21 (614167), caused by mutation in the ZNF644 gene (614159) on 1p22; MYP22 (615420), caused by mutation in the CCDC111 gene (615421) on 4q35; MYP23 (615431), caused by mutation in the LRPAP1 gene (104225) on 4p16; MYP24 (615946), caused by mutation in the SLC39A5 gene (608730) on 12q13; MYP25 (617238), caused by mutation in the P4HA2 gene (600608) on 5q31; and MYP26 (301010), caused by mutation in the ARR3 gene (301770) on Xq13.

Clinical Features

Myopia is, in a sense, a metric character. Variation in many components of the eye contributes to its refractive capacity (Sorsby et al., 1962). High-grade myopia is a refractive error greater than or equal to -6.00 diopters (Young et al., 1998).

Young et al. (1998) studied 8 medium to large multigenerational families with an autosomal dominant pattern of myopia of more than -6.00 diopters. Myopic individuals had no clinical evidence of connective tissue abnormalities, and the average age at diagnosis of myopia was 6.8 years. The average spherical component refractive error for the affected individuals was -9.48 diopters.

Other Features

Karlsson (1975) concluded that the 'myopia gene' may influence brain development. Myopic high school students aged 17 or 18 years performed better on IQ tests than their nonmyopic classmates. Comparison with test results obtained 10 years earlier before development of myopia suggested that the influence of the gene on the brain was of fundamental importance. Cohn et al. (1988) investigated the association between myopia and superior intelligence in the general population in a group of intellectually gifted children and their less gifted full sibs. A highly significant gifted-nongifted sib difference in myopia was found consistent with the hypothesis that intelligence and myopia are related pleiotropically.

Benhamou et al. (2002) used optical coherence tomography (OCT) to follow the macula in high myopia with macular staphyloma. They found outer retinoschisis in all eyes and inner retinoschisis in 6 of 21 eyes. Ten of 21 eyes developed foveal cysts, 6 had lamellar holes, and 6 had foveal detachment. Four of 21 eyes developed foveal traction; 2 of these went on to develop full-thickness macular holes due to tangential traction of the posterior hyaloid. Baba et al. (2003) reported that in highly myopic eyes with posterior staphyloma, the prevalence of foveal retinal detachment without macular hole was 9%. Visual acuity varied and foveal detachment was missed on routine examination. Thus, the authors recommended periodic OCT examination of highly myopic eyes with severe degenerative changes and posterior staphyloma.

Inheritance

Myopia is a complex heterogeneous disorder; both genetic and environmental factors have been implicated (Young et al., 1998).

Autosomal dominant myopia has been reported by Flach (1942), Franceschetti (1953), and Francois (1961). High-grade myopia was transmitted through 4 generations in the family reported by Francois (1961). Franceschetti (1953) observed a family with 10 cases in 4 generations. Four suffered detachment of the retina. DelBono et al. (1995) described 52 2- and 3-generation families with 2 or more individuals affected by juvenile-onset myopia, defined as refractive error of more than -0.75 diopters by age 15 years.

Ip et al. (2007) examined the influences of ethnicity, parental myopia, and 'near work' on spherical equivalent refraction (SER) and axial length (AL) in a population-based sample of 2,353 Australian children (mean age, 12 years). The prevalence of myopia in the children increased with the number of myopic parents. In multivariate analyses, odds of childhood myopia did not change with higher levels of near work. Interactions between parental myopia and ethnicity were significant for SER and AL, reflecting greater decreases in SER and greater increases in AL with the number of myopic parents in the children of East Asian ethnicity (15% of the sample) than in the children of European Caucasian ethnicity (60% of the sample). In the nonmyopic children, there was no association between parental myopia and AL. Thus, in this sample, parental myopia was associated with more myopic SER and longer AL, with significant ethnic interactions.

On the basis of studies in the Finnish Twin Cohort, Teikari et al. (1991) estimated that the heritability of myopia is 0.58 (0.74 for males and 0.61 for females) when myopia is considered a dichotomous variable.

Klein et al. (2005) examined the familial aggregation and pattern of inheritance of ocular refractive error in an adult population using data from the Beaver Dam Eye Study. The results of segregation analyses did not support the involvement of a single major locus throughout the entire range of refractive error; however, models allowing for familial correlation, attributable in part to polygenic effects, provided a better fit to the observed data than models without a polygenic component, suggesting that several genes of modest effect might influence refractive error, possibly in conjunction with environmental factors. Klein et al. (2005) concluded that these results supported the involvement of genetic factors in the etiology of refractive error and were consistent with reports of linkage to multiple regions of the genome.

Kolata (1985) summarized the work of Raviola and Wiesel (1985), which is relevant to the nature/nurture controversy in the area of myopia. Their work with an animal model suggested that myopia is caused by abnormal influences of the nervous system on the developing eye. In studying the effects of visual deprivation on the development of the visual system, they sutured shut the eyes of young monkeys. In the course of this they found that the eyeball grew abnormally long as in myopia. Monkeys with sutured eyes reared in the light became myopic whereas those reared in the dark did not. Distortion of the visual image by injecting small polystyrene beads into the corneal stroma likewise led to myopia. In humans it has been found that children with ptosis become myopic and children with unilateral hemangioma of the eyelid develop myopia in the closed eye. Children with corneal opacities tend to be myopic as do those with mild retrolental fibroplasia which distorts vision. In the rhesus macaque monkey, atropine did not prevent development of myopia; in the stumptailed macaque it did. Section of the optic nerve did not prevent development of myopia in the macaque but did in the stumptail. This was interpreted as indicating that growth factors produced by the retina are important in the former and brain impulses in the latter species; both factors may be operative in man.

Mapping

Young et al. (1998) conducted a genomewide screen for myopia susceptibility loci in 8 medium to large multigenerational families with an autosomal dominant pattern of myopia of more than -6.00 diopters. Candidate loci for the Stickler syndromes, Marfan syndrome, and juvenile glaucoma were also analyzed to exclude linkage to the myopia known to occur with these disorders. Significant linkage to 18p was found. The maximum lod score was 9.59, with marker D18S481, at a recombination fraction of 0.0010. Haplotype analysis further refined this myopia locus to a 7.6-cM interval between markers D18S59 and D18S1138 on 18p11.31.

Young et al. (2001) suggested that the locus for 18p11.31-linked high myopia (MYP2) is most proximal to marker D18S52, with a likely interval of 0.8 cM between markers D18S63 and D18S52. With this contraction of the interval size by transmission disequilibrium tests, the authors concluded that their results provided a basis for focused positional cloning and candidate gene analysis at the MYP2 locus.

Molecular Genetics

Lam et al. (2003) investigated the coding exons of TGF-beta-induced factor (TGIF; 602630), which maps to chromosome 18p, for mutations in Chinese patients with high myopia. Six SNPs showed a significant difference (p less than 0.05) between patient and control subjects in univariate analysis. Only 657T-G showed statistical significance in the logistic regression model (odds ratio 0.133; 95% CI 0.036-0.488; p = 0.002). Lam et al. (2003) concluded that TGIF is a probable candidate gene for high myopia.

Associations Pending Confirmation

In a study of 123 families with a myopic child, defined as myopia of at least -0.75 diopters for inclusion, Mutti et al. (2007) analyzed DNA from 517 individuals for markers and SNPs in regions previously associated with pathologic myopia or in genes associated with syndromes in which myopia is a feature. The most significant association for common, low-degree myopia was found with the major allele of the COL2A1 (120140) SNP rs1635529 on chromosome 12q13.11, which showed highly significant overtransmission to affected individuals (p = 0.00007 for 44 informative families). Mutti et al. (2007) stated that this was somewhat surprising since, typically, myopia is regarded as a condition of excessive axial scleral growth, but the human sclera is predominantly composed of type I collagen with little to no evidence for the presence of type II collagen. The authors further noted that although type II collagen is a primary constituent of vitreous, the vitreous had never been considered a factor in determining refractive error.

Metlapally et al. (2009) investigated the association of COL1A1 (120150) and COL2A1 polymorphisms with myopia in 2 large independent Caucasian multiplex high-grade myopia family datasets. Significant association was identified between 5 SNPs of the COL2A1 gene, rs1034762, rs1635529, rs1793933, rs3803183, and rs17122571, and high-grade myopia (p less than 0.045 for all). No association was found between COL1A1 SNPs and any degree of myopia.

For discussion of a possible association between high myopia and variation in the MYCBP2 gene, see 610392.0001.

Tedja et al. (2018) performed a genomewide association metaanalysis of refractive error in 160,420 participants and replication in 95,505 participants, which increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (greater than 0.78). The most significantly associated variant was rs12193446 (p = 4.21 x 10(-84), replication p = 4.60 x 10 (-106)), an A (effect allele)-G SNP which resides on chromosome 6 within a noncoding RNA sequence, BC035400, in an intron of the LAMA2 gene (156225). The second most significantly associated variant, rs524952 (p = 2.28 x 10(-65), replication p = 1.60 x 10 (-103)), is an A (effect allele)-T SNP that resides on chromosome 15 near the GOLGA8B (609619) and GJD2 (607058) genes. The gene with the highest biological plausibility score was GNB3 (139130), which has been implicated in congenital stationary night blindness (CSNB1H; 617024).

Reviews

See Young (2009) for a review of myopia.