Alternative titles; symbols
ORPHA: 98553, 98942, 98944; DO: 12270;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p13 | Microphthalmia/coloboma 12 | 120200 | Autosomal dominant | 3 | PAX6 | 607108 |
A number sign (#) is used with this entry because of evidence that microphthalmia/coloboma-12 (MCOPCB12) is caused by heterozygous mutation in the PAX6 gene (607108) on chromosome 11p13.
Coloboma is an ocular birth defect resulting from abnormal development of the eye during embryogenesis. It is defined as a congenital defect in any ocular tissue, typically presenting as absent tissue or a gap, at a site consistent with aberrant closure of the optic fissure. Failure of fusion can lead to coloboma of one or multiple regions of the inferior portion of the eye affecting any part of the globe traversed by the fissure, from the iris to the optic nerve, including the ciliary body, retina, and choroid. Coloboma is also frequently associated with small (microphthalmic) or absent (anophthalmic) eyes as part of an interrelated spectrum of developmental eye anomalies, and can affect either one or both eyes (summary by Kelberman et al., 2014).
Microphthalmia/coloboma-12 (MCOPCB12) is characterized by inter- and intrafamilial variability. In addition to microphthalmia and coloboma, other ocular anomalies include iris hypoplasia, aphakia or small lens, lens subluxation, congenital cataract, microcornea, and sclerocornea. Some patients also exhibit neurodevelopmental anomalies (Deml et al., 2016; Williamson et al., 2020).
For a discussion of genetic heterogeneity of colobomatous microphthalmia, see MCOPCB1 (300345).
Barros-Nunez et al. (1995) described a 6-year-old boy in whom bilateral iris coloboma had been observed at birth. Psychomotor development was normal. He showed a typical inferonasal bilateral coloboma of the iris and ciliary body without coloboma of the choroid and retina or optic nerve. Retina, lens, corneal diameters, and visual acuity were normal in both eyes and there were no malformations elsewhere. A male and female first cousin of the proband related through their fathers had iris coloboma and the son of a sister of the father of the proband had unilateral coloboma. The parents in the case of all 3 sibships were normal as were the grandparents. Some unusual molecular mechanism, such as trinucleotide expansion, was suggested, giving the picture of 'delayed mutation' or 'premutation.'
Iris colobomas occur as part of complex malformation syndromes, e.g., iris coloboma with ptosis, hypertelorism, and mental retardation (243310), craniofacial dysmorphism with ocular coloboma, absent corpus callosum, and aortic dilatation (218340), and Hirschsprung disease, microcephaly, and iris coloboma (235730). Yuksel et al. (1999) described 2 female sibs with an MCA/MR syndrome consisting of pre- and postnatal growth retardation, iris colobomata, spasticity, facial dysmorphism, and dilated cerebral ventricles. Coloboma is a prime feature of the CHARGE association (see 214800).
Hornby et al. (2000) correlated visual function with clinical features and biometric findings in the eyes of children with coloboma. Of the 196 eyes with colobomatous malformations, 11 had microphthalmos with cyst (251505), and 185 eyes had coloboma (associated with microcornea in 155 eyes and with normal corneal diameter in 30 eyes). The visual prognosis depended on the phenotype of the more normal eye. Microphthalmos with cyst had the worst prognosis (all worse than 20/400). Microcornea with microphthalmos had a worse prognosis than microcornea without microphthalmos. For microcornea with microphthalmos, 67% saw worse than 20/400. Of the children with microcornea without microphthalmos, 76% saw better than 20/400. Simple coloboma (without microcornea or microphthalmos) had the best visual prognosis: only 7% saw 20/400 or worse. A corneal diameter of less than 6 mm had a poor visual prognosis, whereas a corneal diameter of more than 10 mm had a good prognosis.
Morrison et al. (2000) examined 75 children with iris colobomas. In 13 (17.3%) patients, noticeable iris heterochromia (142500) was present. In patients with unilateral coloboma, the heterochromia was characterized by the darker iris being the one affected with coloboma. In cases of bilateral iris colobomas with clinical microphthalmos and reduced corneal diameter, the variation in iris color was inconsistent. A fundus coloboma was not always present. The authors postulated that the iris coloboma-iris heterochromia association may result from the abnormal closure of the embryonic fissure, resulting in irregular or excessive migration of neural crest cells into the iris stroma. In addition, the high frequency of iris heterochromia-iris coloboma with microphthalmia suggests that an increased density of pigmented cells within the iris stroma may be a contributing factor.
Pigment-dispersion syndrome (600510) and pigmentary glaucoma result from iridozonular friction causing disruption of the iris epithelium and deposition of iris pigment on the anterior segment structures. Tesser (2003) reported a 48-year-old patient with congenital bilateral iris colobomas. Elevated intraocular pressure was present in the eye with a partial iris coloboma and iris transillumination defects but pigment deposition on the ipsilateral corneal endothelium (Krukenberg spindle). The other eye was diagnosed as having mild ocular hypertension, without pigment dispersion or glaucoma, in association with a complete iris coloboma. Tesser (2003) concluded that pigment dispersion was prevented in the eye with the complete iris coloboma.
Azuma et al. (2003) reported a 1-year-old boy (patient 3) with ocular coloboma and mutation in the PAX6 gene. The proband had bilateral iris anomaly, large chorioretinal and optic nerve coloboma, and a remnant of hyaloid vessel proliferation (persistent hyperplastic primary vitreous; see 221900). In addition, he experienced growth retardation and impaired intellectual development.
Gregory-Evans et al. (2004) provided a detailed review of the molecular genetics of ocular coloboma, including a list of inherited disorders and syndromes in which coloboma is a feature.
Deml et al. (2016) reported 2 brothers with microphthalmia and coloboma and mutation in the PAX6 gene. Both brothers exhibited bilateral microphthalmia, iris hypoplasia, sclerocornea, and congenital glaucoma. Optic nerve coloboma and primary aphakia were bilateral in the 6-year-old proband and unilateral in his 4-year-old brother; the younger brother had subluxation of the lens in the other eye. Both boys had extraocular anomalies, including low-set prominent ears and microcephaly in the proband, and asymmetric facies and a history of mild developmental delays that resolved in his younger brother.
Williamson et al. (2020) reported 17 patients from 15 families in the Medical Research Council Human Genetics Unit (HGU) eye malformation cohort who had bilateral microphthalmia, anophthalmia, or coloboma (MAC) and mutation in the PAX6 gene. Ocular features included nystagmus; microphthalmia with or without iris defects; coloboma of the iris, choroid, retina, and/or optic nerve; aphakia, small lens, or lens subluxation; congenital cataract; microcornea; and sclerocornea. Less common eye findings included anterior segment dysgenesis, aberrant retinal vessel pattern, foveal hypoplasia, persistent fetal vasculature, intraocular hypertension, and secondary glaucoma. Neuroimaging was performed in 5 patients and revealed brain anomalies in 4 of them, including small optic nerves, chiasm, and tracts, hypoplasia of the corpus callosum, and slightly enlarged lateral ventricles. Other extraocular features were reported in 6 patients, including reduced head circumference, autistic behaviors, developmental delay, and mildly to severely impaired intellectual development.
Pedigrees supporting dominant inheritance have been reported. Eldridge (1967) observed an affected family with a dominant pedigree pattern. Snell (1908) observed 12 cases in 5 generations.
The estimated prevalence of coloboma is 1 in 10,000 (Stoll et al., 1997).
Kelberman et al. (2014) stated that coloboma is estimated to account for 3 to 11% of blindness in children worldwide. The prevalence varies by population, ranging from 4 to 19 per 100,000 live births across Europe with higher rates reported in populations with a high degree of consanguinity.
Arias et al. (1984) studied a patient with de novo deletion of chromosome 2pter-p25.1. ACP1 (171500) and MDH1 (154200) levels were normal, suggesting that these loci are proximal to 2p25.1. The child had bilateral coloboma of the iris.
Azuma et al. (2003) identified a heterozygous mutation in the PAX6 gene (607108.0019) in a 1-year-old boy who had iris anomaly, large coloboma of the optic nerve (120430), retina, and choroid, a remnant of hyaloid vessel proliferation (persistent hyperplastic primary vitreous) bilaterally, and growth and mental retardation.
In a cohort of 28 probands with microphthalmia, anophthalmia, and/or coloboma (MAC), Deml et al. (2016) performed whole-exome sequencing and identified a heterozygous missense mutation in the PAX6 gene (V256A; 607108.0027) in a 6-year-old boy (patient 1) and his affected 4-year-old brother. Both parents were unaffected, and DNA analysis by Sanger sequencing indicated that the mother was a likely mosaic carrier of the mutation, which was not found in public variant databases.
From among 372 individuals with bilateral MAC in the HGU eye malformation cohort, Williamson et al. (2020) identified 17 patients from 15 families who were heterozygous for missense mutations in the PAX6 gene (see, e.g., 607108.0026 and 607108.0028-607108.0033). Six probands had de novo mutations and 2 probands inherited the mutation from an affected parent; no segregation information was available for the remaining families. Analysis of a group of 399 unrelated individuals from the HGU eye malformation cohort who had aniridia (see 106210) or other PAX6-associated ocular anomalies revealed 7 non-MAC patients from 3 families with heterozygous missense mutations in PAX6. The authors also reviewed likely causative PAX6 missense variants reported in the Deciphering Developmental Disorders study, and reported 7 patients with heterozygous mutations in PAX6 (see 607108.0004 and 607108.0033). Functional analysis showed reduced binding to known DNA targets with the mutant proteins compared to wildtype PAX6. Williamson et al. (2020) noted that the remarkable sequence diversity of in vivo PAX6 binding sites might result in variant-specific differential effects on both the degree and repertoire of target gene activation; however, they stated that molecular properties alone could not explain all of the phenotypic heterogeneity observed among PAX6 missense variants, noting that patients with the same variant exhibited very different phenotypes.
Associations Pending Confirmation
Asai-Coakwell et al. (2007) characterized a chromosome 8q21.2-q22.1 segmental deletion in a patient with chorioretinal coloboma and found elements of nonallelic homologous recombination and nonhomologous end joining. They demonstrated that the segmental deletion encompasses GDF6 (601147), and that inhibition of gdf6a in zebrafish accurately recapitulated the proband's phenotype. The spectrum of disorders generated by morpholino inhibition of gdf6a and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrated the key role of GDF6 in ocular development. In Xenopus, Hanel and Hensey (2006) demonstrated that inhibition of gdf6 resulted in ocular developmental anomalies.
Ye et al. (2010) screened DNA samples from 449 probands with isolated microphthalmia and/or coloboma and 23 probands with skeletal or oculoskeletal phenotypes for mutations in the GDF3 gene and identified a heterozygous missense mutation (L305P; see 606522.0002) in an Asian female with bilateral iris coloboma.
Arias, S., Rolo, M., Gonzalez, N. Terminal deletion of the short arm of chromosome 2, informative for acid phosphatase (ACP1), malate dehydrogenase (MDH1), and coloboma of iris loci. (Abstract) Cytogenet. Cell Genet. 37: 401 only, 1984.
Asai-Coakwell, M., French, C. R., Berry, K. M., Ye, M., Koss, R., Somerville, M., Mueller, R., van Heyningen, V., Waskiewicz, A. J., Lehmann, O. J. GDF6, a novel locus for a spectrum of ocular developmental anomalies. Am. J. Hum. Genet. 80: 306-315, 2007. [PubMed: 17236135] [Full Text: https://doi.org/10.1086/511280]
Azuma, N., Yamaguchi, Y., Handa, H., Tadokoro, K., Asaka, A., Kawase, E., Yamada, M. Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations. Am. J. Hum. Genet. 72: 1565-1570, 2003. [PubMed: 12721955] [Full Text: https://doi.org/10.1086/375555]
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Deml, B., Reis, L. M., Lemyre, E., Clark, R. D., Kariminejad, A., Semina, E. V. Novel mutations in PAX6, OTX2 and NDP in anophthalmia, microphthalmia and coloboma. Europ. J. Hum. Genet. 24: 535-541, 2016. [PubMed: 26130484] [Full Text: https://doi.org/10.1038/ejhg.2015.155]
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Williamson, K. A., Hall, H. N., Owen, L. J., Livesey, B. J., Hanson, I. M., Adams, G. G. W., Bodek, S., Calvas, P., Castle, B., Clarke, M., Deng, A. T., Edery, P., and 19 others. Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction. Genet. Med. 22: 598-609, 2020. [PubMed: 31700164] [Full Text: https://doi.org/10.1038/s41436-019-0685-9]
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