Genetics of the Retinal Dystrophies


The inherited retinal dystrophies (IRDs) are a group of heterogeneous disorders that individually are rare, but collectively have an incidence of 1 in 2000–3000 affecting an estimated 2 million people worldwide. The main cause of vision loss is the death or dysfunction of the photoreceptors, the rods and cones, leading to either partial or total blindness. To date, over 260 genes underlying the monogenic forms of IRDs have been identified, but there are still many to find. These disorders exhibit a wide range of phenotypes with significant overlap, but they can be broadly subdivided on the basis of retinal cell type affected. Understanding the underlying genetic cause enables patients to get a definitive diagnosis and in turn allows the development of therapies targeted to a specific gene defect, with both gene therapy and gene‐editing techniques showing great potential and suggesting a promising future for people living with these conditions.

Key Concepts

  • The retina is the photosensitive tissue that lines the inside of the eye; it is multilayered and is composed of highly specialised cells that receive and process light information.
  • The inherited retinal dystrophies are a group of diseases that individually are rare, but collectively affect approximately 2 million people worldwide.
  • The main cause of vision loss is the death or dysfunction of the photoreceptors, the rods and cones, leading to either partial or total blindness.
  • Most inherited retinal dystrophies have been found to be caused by monogenic mutations in genes, although more complex forms, such as age‐related macular degeneration (AMD), caused by an interplay of genetic, environmental and lifestyle factors, also exist.
  • To date, more than 260 genes have been identified that cause monogenic retinal degeneration in humans.
  • The most common inherited retinal degeneration is retinitis pigmentosa (RP). More than 70 genes have been found to cause RP and can be inherited in an X‐linked, autosomal dominant or autosomal recessive manner.
  • IRDs exhibit both genetic and phenotypic heterogeneity, meaning that different genes can cause the same disease, and the same mutation can cause different disease phenotypes in different individuals. This means that there is a significant overlap between disorders often making a clear‐cut diagnosis difficult.
  • Recent advances in molecular genetics have seen gene therapy trials show some success in patients, but most conditions remain without a cure; however, recent advances in molecular technology have improved our understanding of IRDs and will further aid development of therapies with gene‐editing techniques an exciting prospect.

Keywords: retina; genes; mutations; retinitis pigmentosa; photoreceptor; inherited retinal dystrophies; vision; gene therapy; genome editing

Figure 1. Cross section of the human eye. Light travels through the clear cornea and is focused by the lens (adjusted by the ciliary muscle) onto the retina. In humans and primates, most light is focused onto the cone‐rich fovea which mice lack.
Figure 2. Anatomy of the mammalian retina. (a) Nuclear layers of the retina. Haematoxylin and eosin staining of P21 mouse retina cross section showing the three cell layers (outer nuclear layer (ONL), inner nuclear layer (INL) and ganglion cell layer (GCL)) separated by the two neuropils (outer plexiform layer (OPL) and inner plexiform layer (IPL)) where synaptic connections between cells occur. (b) Cell types of the retina. Rod and cone photoreceptors form synaptic connections with bipolar and horizontal cells in the OPL. Bipolar cells carry their signals to the amacrine and ganglion cells in the IPL, and then ganglion cell axons carry signals to the brain via the optic nerve. Müller glia provide structural support to the other retinal neurons.


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Further Reading

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Merepa, Solomon S, Broadgate, Suzanne, Sekaran, Sumathi, and Halford, Stephanie(Jun 2018) Genetics of the Retinal Dystrophies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028116]