A number sign (#) is used with this entry because of evidence that autosomal recessive ocular coloboma is caused by homozygous mutation in the SALL2 gene (602219) on chromosome 14q11. One such family has been reported.

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 1 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).

For a discussion of genetic heterogeneity of ocular coloboma, see 120200.

Kelberman et al. (2014) studied a consanguineous Kuwaiti family in which 3 sibs exhibited nonsyndromic coloboma. The oldest affected sib, who was examined at 13 years of age, presented with bilateral typical inferior iris coloboma and marked retinochoroidal coloboma. In addition, she had mild lens opacity, bilateral manifest-latent nystagmus, and left exotropia with poor fixation in the left eye. Visual-evoked potentials (VEPs) and visual acuity were reduced on the left. Her 11-year-old brother had bilateral retinochoroidal and optic disc coloboma, subluxation of the right lens, esotropia and hypertropia of the right eye, and bilateral rapid manifest-latent nystagmus. VEPs were poor on the left and moderate on the right, and visual acuity was more reduced on the left (20/200) than the right (20/40). Her 9-year-old brother had severely decreased vision in his left eye (hand movements only) associated with a large retinochoroidal coloboma involving the optic disc; the right fundus appeared normal, with a visual acuity of 20/125. In addition, he had hypertropia, variable esotropia, and manifest-latent nystagmus on the left. VEPs were consistent with very rudimentary vision on the left. He also had a small left cornea, but axial length of that eye was not measured. Full pediatric review of the 3 affected sibs showed no neurologic, developmental, or renal abnormalities. Ophthalmologic examination of their unaffected first-cousin parents and 3 other brothers showed no abnormalities.

Pagon et al. (1981) reported ocular coloboma in a brother and sister with unaffected and unrelated parents; the authors suggested possible recessive inheritance.

The transmission pattern of ocular coloboma in the family reported by Kelberman et al. (2014) was consistent with autosomal recessive inheritance.

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.

In a consanguineous Kuwaiti family in which 3 sibs exhibited nonsyndromic coloboma, Kelberman et al. (2014) performed homozygosity mapping and identified 2 loci that were greater than 2 Mb in size and common to all 3 affected sibs: a 5.3-Mb segment on chromosome 8p11.1, and a 15.5-Mb region on chromosome 14q11.2.

In an affected individual from a consanguineous Kuwaiti family with coloboma linking to either chromosome 8p11 or 14q11, Kelberman et al. (2014) performed exome sequencing and identified a single coding variant within the largest region of homozygosity on chromosome 14: a nonsense mutation in the SALL2 gene (E29X; 602219.0001). The mutation, which was confirmed by Sanger sequencing, was shown to be homozygous in all 3 affected sibs and heterozygous in both parents; DNA from the 3 unaffected sibs was unavailable for analysis. The variant was not found in 6,500 exomes from the NHLBI Exome Variant Server database. Analysis of SALL2 in 178 patients with coloboma and associated anophthalmia/microphthalmia phenotypes revealed no pathogenic variants.

Kelberman et al. (2014) generated Sall2 (602219)-null mice and observed no overt phenotypic abnormalities; however, histologic analysis of the eyes revealed a colobomatous phenotype, with delayed apposition of the optic fissure margins and persistence of an anterior retinal coloboma phenotype after birth. There was no evidence for a small eye phenotype in any of the homozygous Sall2-null mutant eyes at either the embryonic or adult stage.