Microphthalmia, Isolated, With Coloboma 9

A number sign (#) is used with this entry because of evidence that nonsyndromic microphthalmia with coloboma-9 (MCOPCB9) and microphthalmia and/or coloboma with developmental delay (MCOPS15) are caused by homozygous mutation in the ODZ3 gene (TENM3; 610083) on chromosome 4q35. One family with MCOPCB9 has been reported.

For a discussion of genetic heterogeneity of isolated colobomatous microphthalmia, see MCOPCB1 (300345).

Description

MCOPCB9 is characterized by isolated microphthalmia and coloboma (Aldahmesh et al., 2012). MCOPS15 is characterized by microphthalmia and/or coloboma, with developmental delay in which speech appears to be more severely affected than motor abilities. Additional ocular anomalies that have been observed include ptosis, keyhole-shaped pupils, microcornea, sclerocornea, and anterior segment dysgenesis (Chassaing et al., 2016; Stephen et al., 2018; Singh et al., 2019).

Clinical Features

Isolated Microphthalmia and Coloboma 9

Aldahmesh et al. (2012) reported a Saudi Arabian brother and sister, born of third-cousin parents, who had nonsyndromic bilateral colobomatous microphthalmia. The 11-year-old brother had no medical history other than congenitally small eyes and accompanying poor vision, with 20/50 visual acuity on the right and hand motion on the left; similarly, his 9-year-old sister had visual acuities of 20/200 and 20/300 on the right and left, respectively. Anterior segment examination of both sibs revealed microcornea, microphthalmos, and iris coloboma, and funduscopic examination showed grossly anomalous discs and total coloboma involving the macula. Both sibs had normal cognitive and motor development. Their parents had normal eyes upon examination, and there were 2 other unaffected sisters.

Syndromic Microphthalmia 15

Chassaing et al. (2016) reported a 9-year-old boy, born of first-cousin parents, who had bilateral colobomatous microphthalmia noted at birth and developed pendular nystagmus and esotropia. Examination revealed bilateral microcornea and iris coloboma with clear lenses, as well as bilateral optic disc and chorioretinal colobomas involving the macula. Both eyes were myopic. At age 2 years, he developed a retinal detachment in the left eye, and at age 8, a retinal detachment in the right eye. Visual acuity was estimated at hand movements bilaterally at age 9, and he also exhibited developmental delay with intellectual disability.

Stephen et al. (2018) studied 2 sisters with vertically oval microcornea, inferonasal iris coloboma, keyhole-shaped pupils, and inferomedial retinal coloboma, which involved the optic discs and fovea in one sister and spared those in the other. The older sister had unilateral ptosis, whereas the younger sister had bilateral partial ptosis and left convergent squint. Axial lengths were not reported. Dysmorphic features included broad eyebrows, hypertelorism, narrow palpebral fissures, long philtrum, and low-set flared pinnae. Both sisters exhibited developmental delay, with the younger sister showing mild motor delay and more significant speech delay, with only a few words at age 4 years. A maternal uncle had severe vision loss and was reported to have had small eyes.

Singh et al. (2019) reported a 9-year-old Indian boy who presented at age 6 years with severe global developmental delay and ocular malformations that had been noted at birth. Examination revealed dysmorphic features including plagiocephaly, low anterior hairline, supraorbital flattening, and large ears. He had right microphthalmia, bilateral sclerocornea, and anterior segment dysgenesis. He walked at 3 years of age and was toilet trained by age 7; speech delay was more severe, with only 10 words and inability to make sentences at age 9. Brain MRI did not show any intracranial abnormality.

Molecular Genetics

Isolated Microphthalmia and Coloboma 9

In a Saudi Arabian brother and sister with nonsyndromic bilateral colobomatous microphthalmia, who were negative for mutation in known microphthalmia genes, Aldahmesh et al. (2012) performed combined autozygome and exome analysis, which revealed homozygosity for a frameshift mutation in the ODZ3 gene (610083.0001). Their unaffected parents were heterozygous for the mutation, which was not found in ethnically matched controls or in the Exome Variant Server.

Syndromic Microphthalmia 15

In 96 patients with microphthalmia, Chassaing et al. (2016) analyzed 187 genes associated with ocular development and identified homozygosity for a splice site mutation in the TENM3 gene (610083.0002) in a 9-year-old boy with bilateral colobomatous microphthalmia. His unaffected first-cousin parents and an unaffected sister were heterozygous for the mutation. The patient also exhibited intellectual disability, which the authors noted might be an inconstant feature associated with TENM3 mutation, or the result of other genetic variants in this consanguineous family.

In 2 sisters with ocular coloboma and microcornea as well as developmental delay, Stephen et al. (2018) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the TENM3 gene (C619X; 610083.0003) that segregated with disease in the family.

By exome sequencing in a 9-year-old Indian boy with unilateral microphthalmia, bilateral sclerocornea, anterior segment dysgenesis, and severe developmental delay, Singh et al. (2019) identified compound heterozygosity for 2 missense mutations in the TENM3 gene (A1349G, 610083.0004 and R2563W, 610083.0005). His unaffected father and brother were heterozygous for the A1349G mutation, whereas his unaffected mother did not carry either mutation, suggesting mosaicism in the mother or occurrence of a de novo variant in the proband.