The molecular genetics of eye diseases

This review issue of Human Molecular Genetics focuses on the eye. Perhaps the study of no other organ system has benefited more from the combination of the results of the Human Genome Project and recent progress in molecular biology. Conversely, the study of the eye has provided great insight into disease pathophysiology and the understanding of genomics. These statements are not surprising when one considers the following facts: (i) the eye is composed of many cell types, and approximately 90% of the genes in the human genome are expressed in one or more of the many tissues composing the eye during development and/or in maturity; and (ii) approximately one-third of the clinical disorders catalogued in Online Mendelian Inheritance in Man (OMIM) list a feature involving the eye (1). Progress has been made in understanding inherited eye diseases displaying nearly every type of inheritance pattern including X-linked, autosomal dominant and recessive, mitochondrial, digenic and complex. In fact, several eye diseases display all of these inheritance patterns.

Advantages in studying eye pathophysiology and function include the facts that eye disease can result in a noticeable deficit observable by the patient or the patient’s parents even at a young age; and ophthalmologists can readily and non-invasively evaluate eye anatomy and key structures with ophthalmoscopy, electrophysiology, and more recently, with optical coherence tomography (OCT). Application of state-of-the-art molecular genetics and molecular biology to inherited eye disorders including positional cloning methods, genome-wide association studies, and whole exome sequencing has led to the discovery of hundreds of genes and thousands of mutations in hundreds of diseases. A review of the topic in Human Molecular Genetics is long overdue.

Reviewed in the various articles in this issue of HMG are topics impacting many aspects of this complex organ including photoreceptors and the photoreceptor outer segment; retinopathies; macular degeneration; corneal diseases; congenital, developmental and primary open angle glaucomas; the complement system in eye disease; mitochondrial dysfunction; ocular congenital dysinnervation disorders; genetic modifiers of eye phenotypes, and others. Important points to observe as one reads the articles are the large variety of disorders impacting the eye, the diversity of phenotypes and ages of onset observable even with mutations in the same gene, and in other instances, the diversity of genes resulting in the same or very similar clinical presentations. Also apparent in the molecular genetics of inherited eye diseases, as in most fields of medicine and science, is the fact that many challenges remain in developing treatments for eye diseases, perhaps none greater than the development of cost effective molecular therapies (2) for these disorders that impact the quality of life for many patients. Hope lies in the fact that many features of the eye make it an outstanding target for molecular and cell therapies and that novel approaches have been and are being developed.