Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Abstract

Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counselling challenging. In this review, we present the main genes implicated in nonsyndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.

A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye

“…In conclusion, the bilateral colobomata in our patient might well be a part of the clinical spectrum of Steel syndrome, even if our molecular evidence is only indirect and hypothetical, and does not rule out random coincidence, which is noteworthy given that genetic analyses of patients with colobomata prove the molecular basis in up to 75% of severe cases but only in 20–30% of milder cases of eye malformations from the anophthalmia/microphthalmia/coloboma spectrum (Harding, Brooks, FitzPatrick, & Moosajee, ; Plaisancié et al, ). We suggest detailed ophthalmological investigations in all individuals with this condition in order to investigate a possible association between structural eye defects and Steel syndrome.…”

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

“…The development of the human eye is controlled by a morphogenetic process that requires precise spatial and temporal gene regulation [1,2]. Perturbation of early eye organogenesis due to genetic factors can result in halting of eye development or multiple eye tissues disorders, and among them degenerations of the retina occupies a special place [3][4][5]. Inherited eye diseases make up a clinically and genetically heterogeneous group of diseases and mutations in which over 260 genes have been proven to be causative.…”

Three novel mutations of microphthalmos identified in two Chinese families

“…Genetic alterations are now a major cause of microphthalmos. The hereditary mode of nanophthalmos is autosomal dominant in many patients and sporadic in others [5,6]. As a developmental eye disease, most of the related genes involved in microphthalmos are also ocular developmentassociated genes, including SOX2, OTX2, PAX6, and GJA8.…”