Explainer: South Africa’s challenges in the search for genes causing eye disease

A visually impaired young girl reads a Braille notice. Retinal dysfunction results in one in 3 500 people suffering night blindness, loss of peripheral vision and later complete blindness. Reuters/Amr Abdallah Dalsh

The retina is a thin, light-sensitive tissue at the back of the eye. It captures light and converts it into a chemical signal which travels to the brain, ultimately registering as vision. The retina is actually part of the central nervous system and is considered part of the brain. The ‘photoreceptors’ or light-sensitive nerve cells of the retina, are divided into the rod cells and the cone cells, reflecting their actual shapes.

There are about 120 million rod cells spread throughout the retina. These are responsible for black and white vision, and allow vision in low-light conditions. Then the six million cone cells are located in the centre of the retina, in an area called the macula, and are responsible for colour vision and detailed central vision.

A group of diseases collectively called inherited retinal degenerative disorders are caused by genetic defects which cause vision loss. This may result in total blindness. These disorders are caused by genetic changes or mutations and are inherited within families.

These genetic mutations result in different disorders. Gene defects affecting mainly the rod photoreceptors cause retinitis pigmentosa. As a result patients experience night blindness and loss of peripheral vision, causing a tunnel-like vision. Genetic mutations causing a primary loss of cone photoreceptors result in Stargardt disease or macular degeneration and cause a loss of central vision.

A rare disease without a cure

Although genetic diseases are generally rare, globally about 1 in 3500 people suffer from retinal degenerative disorders. In South Africa and Africa, exact statistics around retinal degenerative disorders are not available. We estimate that at least 14 500 South Africans suffer from vision loss because of these disorders. This conservative estimate is based on reported retinal degenerative disorders cases but each disorder has a different incidence rate so this number is likely higher.

There is currently no cure for retinal degenerative disorders but many gene therapies for these diseases are being established. In gene therapy the mutation in a gene has been corrected and is inserted into a patient’s cells as a treatment for disease.

There are at least eight clinical trials across the globe in countries such as the US. These trials are testing the safety and efficacy of gene therapies in patients with these disorders.

Advances in treatment

The use of gene therapy for eye diseases are further advanced than for most other diseases. This is because the eye is small, easily accessible and self-contained. This means small amounts of treatment with the corrected gene can be inserted directly where needed.

There is little worry about unwanted off-target effects - where other sites in the genome are unintentionally modified - because the treatment does not cross the blood-brain barrier and cannot enter the rest of the body. This is the biggest concern within the gene therapy field.

But to participate in any of these trials, the patient must have a confirmed genetic diagnosis, meaning a confirmed mutation in the gene which is to be replaced or repaired.

The genetic cause of these disorders must be identified in South Africans for the clinical trials to come to the country - a process that Retina South Africa has been intricately involved in.

Complicated genetics in retinal dysfunction

There are several challenges in identifying the genes causing retinal degenerative disorders in families.

The first is that the genetics of these disorders are complex. There are more than 280 genes reported to be linked to these disorders. Mutations in any one of those genes can cause these disorders. There are potentially hundreds of mutations in each gene. Some genes are obvious candidates involved in the cells or biological pathways required for vision. Others are unlikely culprits and are responsible for normal functioning of cells in the body. They cause no other disease besides retinal dysfunction and subsequent vision loss.

Secondly, retinal degenerative disorders can be inherited in families in different ways. They can also manifest as part of a syndrome such as Usher syndrome, which involves both vision impairment and hearing loss.

An ophthalmologist cannot tell from a clinical examination what the genetic cause of the disorder is. Patients with different mutated genes can end up with the same clinical disease. For example, more than 55 different genes can each cause retinis pigmentosa. What further complicates this is within families, people with the same genetic mutation can have different symptoms.

And as the disease progresses over time the symptoms change, which can result in a change of the disease diagnosis.

Making a genetic diagnosis is challenging and requires detailed clinical information and family history. But having a genetic diagnosis is essential to participate in any gene therapy based clinical trials.

The South African challenge

Finding a genetic diagnosis is also complicated by the unique genetic diversity of Africans. Most white South Africans originated from European settlers so our testing for the specific genetic mutations reported internationally has been successful over the last 26 years of research at the University of Cape Town.

But there is less success with this approach for black South Africans. African populations have vast genetic diversity, as a result of admixture between populations and migration around, out of and back into Africa.

Our current research with Professor Anand Swaroop at the National Eye Institute in the US uses the next generation of DNA sequencing technology to sequence the entire coding region of the human genome, known as the exome, in black South Africans.

The exome is the one to two percent of the human genome containing active portions of all 20 000 known human genes. By sequencing the exome of this unique patient population group, we hope to identify their genetic basis of retinal degenerative diseases, which may have relevance to the continent as a whole.

This is a new technology and local scientists require collaboration and training in the analysis, as well as major computational resources. It is an approach which does not rely purely on our existing knowledge of retinal degenerative disorder genes but includes all human genes, both likely and unlikely candidates.