Microphthalmia, Isolated 8

A number sign (#) is used with this entry because of evidence that isolated microphthalmia-8 (MCOP8) is caused by homozygous mutation in the ALDH1A3 gene (600463) on chromosome 15q26.

For a general phenotypic description and a discussion of genetic heterogeneity of isolated microphthalmia, see MCOP1 (251600).

Clinical Features

Fares-Taie et al. (2013) studied a consanguineous Pakistani family in which the proband was a girl born with severe bilateral clinical anophthalmia. Cerebral MRI at 1 week of age showed small optic nerves and a small optic chiasm. Autism was diagnosed at 3 years of age. There were 2 healthy sisters in the family, and a fourth pregnancy was terminated due to detection of apparent bilateral anophthalmia with normal brain structures on prenatal ultrasound. A maternal cousin was also born with severe bilateral microphthalmia; he had a rudimentary globe on the left and a grossly abnormal globe associated with a cyst on the right. In addition, he had moderate pulmonary and supravalvular pulmonary stenosis and a moderately sized atrial septal defect. At 4 years of age, he was given a possible diagnosis of autism. Fares-Taie et al. (2013) also studied a consanguineous Turkish family in which the proband was a girl with bilateral microphthalmia, more severe on the right. She had no other health problems and displayed normal intelligence. A maternal uncle had died at age 1 month with bilateral clinical anophthalmia. In a third consanguineous family of Moroccan ancestry, the proband had severe bilateral microphthalmia, associated with a cyst on the left. MRI showed dysplastic globes and a hypoplastic chiasm and optic nerves, with the remainder of the brain appearing normal. She had no other health problems and was of normal intelligence.

Mapping

In a consanguineous Pakistani pedigree with bilateral severe microphthalmia in which mutation in 7 microphthalmia-associated genes had been excluded, Fares-Taie et al. (2013) performed homozygosity mapping and obtained a lod score greater than 3 at a 3.8-Mb region on chromosome 15q26.3 that was confirmed by analysis of informative microsatellite markers.

Molecular Genetics

In the proband from a consanguineous Pakistani pedigree with bilateral severe microphthalmia mapping to 15q26.3, Fares-Taie et al. (2013) performed whole exome sequencing and identified homozygosity for a missense mutation in the ALDH1A3 gene (R89C; 600463.0001) that was confirmed by Sanger sequencing and also found in an affected fetus from a terminated pregnancy and an affected cousin. The proband's unaffected parents were heterozygous for the mutation as was 1 unaffected sib; her other unaffected sib did not carry the mutation. Analysis of ALDH1A3 in 23 additional patients with microphthalmia identified 1 Turkish and 1 Moroccan proband who were homozygous for a missense mutation (A493P; 600463.0002) and a splice site mutation (600463.0003), respectively. The 3 mutations were not found in SNP databases, in the Exome Variant Server, or in 200 control chromosomes. Fares-Taie et al. (2013) noted that additional features present in affected individuals from the Pakistani pedigree such as autism, seen in 2 patients, and cardiac anomalies, present in 1, might be unrelated to alteration in ALDH1A3.

In 2 Egyptian brothers, 1 with bilateral anophthalmia and the other with right anophthalmia and left microphthalmia, posterior coloboma, and detached retina, Yahyavi et al. (2013) performed exome sequencing and identified homozygosity for a nonsense mutation in the ALDH1A3 gene (K190X; 600463.0004). The mutation was not found in the unaffected parents, in 92 Egyptian control chromosomes, or in 384 European chromosomes. In a 4.5-year-old Hispanic girl with bilateral anophthalmia and hypoplasia of the optic nerves and chiasm, Yahyavi et al. (2013) identified homozygosity for a nonsense mutation in ALDH1A3 (K389X; 600463.0005) by whole-genome sequencing in regions where loss of heterozygosity had been detected. The mutation, which was present in heterozygosity in her unaffected parents, was not found in 120 control chromosomes. Yahyavi et al. (2013) generated Aldh1a3-knockdown zebrafish, which displayed a significant reduction in eye size. The phenotype that could be rescued by wildtype ALDH1A3 mRNA, but not by mRNA containing the K190X or K389X mutations, indicative of likely loss of function caused by the mutations.

Animal Model

In zebrafish larvae injected with antisense morpholinos (MOs) against Aldh1a3, Yahyavi et al. (2013) observed a significant reduction in eye size at 48 to 72 hours postfertilization compared to wildtype larvae. Additional phenotypes seen with variable penetrance in morphants included delayed closure of the optic fissure, coloboma-like lesions, cardiac edema, and kinking of the tail. Confocal imaging at 5 days postfertilization showed that the tectum from wildtype larvae was filled with retinal axons and the optic tract had branched into stereotyped fascicles, whereas the tectum from MO-treated larvae appeared less innervated. The morphant phenotype was rescued by wildtype human ALDH1A3 mRNA.