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Introduction

The aim of our research is to improve our understanding of the genetic basis of severe eye malformations in humans and provide logical approaches to molecular diagnosis and genetic counselling. A secondary aim is to identify genes that are critical for human eye development in order to improve our understanding of normal ocular morphogenesis.

Background

Anophthalmia (absent eye), microphthalmia (small eye), congenital cataracts (opacity of the lens), sclerocornea (total opacity of the cornea), coloboma (failure of optic fissure closure) and aniridia (where the iris does not develop) are the main forms of severe eye malformations that we study; each of which can cause visual impairment. In individuals where an eye has developed, various combinations malformation may been seen within the same eye. Where both eyes are affected the severity can vary dramatically and the type of malformation can vary to some extent. These malformations are rare with a total birth incidence of 1 in 5000 but have a significant medical and economic impact on both affected individuals and society. In the developing world congenital infection or vitamin deficiency remain significant etiological factors. However, genetic causes (both chromosomal and single gene disorders) account for most cases in developed countries.

Genetic Causes

My research group have identified genetic changes in the gene SOX2 as a major cause of severe bilateral eye malformations accounting for 20-30% of cases. We have also identified mutations in YAP1 and MAB21L2 as important but rarer causes and been involved in the discovery of OTX2, PAX6 and STRA6 as major genes. Other research groups have identified ALDH1A3, RAX and VSX2 as autosomal recessive form of microphthalmia. However, the precise cause can be identified in only a minority of cases (<40% of the total number of cases). The lack of a precise molecular diagnosis means that an adequate explanation cannot be provided to the individual and their families and that accurate genetic counselling is not possible. The purpose of our research is to improve the molecular diagnostic tests available to affected families and to identify genes that are critical to human eye development. We have written a recent review of the genes that cause eye malformations in the European Journal of Medical Genetics