Genomics in Ophthalmology

While genetics looks at individual genes, genomics refers to the study of all of a person’s or organism’s DNA. Genomic analysis can provide a more comprehensive view of health and disease.

Rapid advances in our knowledge and the increased availability and affordability of testing mean that genomics is increasingly important and relevant within all specialities.

Genomic information is increasingly used in the clinic to inform diagnosis, risk stratification and treatment selection.

Genomics plays a role in the rare eye conditions that are seen by all ophthalmologists from time to time and provides opportunities in terms of management, diagnosis and screening. There are, broadly, two groups of inherited eye conditions:

  1. Rare eye conditions which are collectively important in ophthalmology and often present in children. These include congenital cataract, childhood glaucoma and inherited retinal disease, including macular dystrophies and retinitis pigmentosa.
  2. Later onset conditions, such as age-related macular disease and primary open-angle glaucoma, which also have a strong genetic basis.

Genomic - as opposed to genetic - testing (ie testing multiple genes at the same time) has rapidly improved diagnostic rates over recent years in ophthalmology.

Genomics is becoming increasingly important and testing should be offered to anyone who is eligible and would benefit. Patients with rare diseases are increasingly aware of the power of genomics to help them find a diagnosis.

Inherited eye disorders are highly heterogeneous. Using genomics to find a precise diagnosis for an individual can inform specific treatment and management and determine whether or not family members should be tested and managed, too.

A precise molecular stratification of LCA allows for the identification of those individuals who are susceptible to systemic complications.

  • Timothy was born with poor vision and was diagnosed with LCA. Genomic testing became available on the NHS when he was eight years old. Sequencing results demonstrated that he had a mutation in IQCB1 which is a gene that, when faulty, causes a form of LCA that is often complicated by renal disease and progressive renal failure.
  • At that stage he was referred to the renal physicians who found that his kidneys were scarred and their function severely compromised. He was going to require renal transplantation, which has a much better long-term outcome when undertaken prior to an individual being in acute renal failure. Within 12 months he had received a renal transplant from his mother.
  • Here we can see that Timothy’s management was directed by genomic test results. Importantly, his family members are cared for appropriately in line with his genomic diagnosis, too. Timothy’s sister also has LCA and has poorly functioning kidneys and is now being closely monitors by the paediatric renal service.

Around 30% of children with bilateral congenital cataract have an underlying syndromic diagnosis resulting in significant extraocular complications. Amongst these are a number of rare biochemical conditions that are hard to recognise in childhood, such as Cerebrotendinous xanthomatosis. Such disorders are potentially treatable, especially if recognised early. Genomic analysis enables improved identification of underlying causes of inherited forms of genetic cataract.

  • Two brothers were found to have juvenile onset cataracts. They shared a complicated phenotype that was also associated with developmental delay and progressive behavioural difficulties.
  • Genomic testing, performed after over 20 other diagnostic tests - all found to be normal, efficiently enabled a diagnosis of Cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive genetic disorder caused by an abnormality in the CYP27A1 gene that results in a deficiency of the mitochondrial enzyme sterol 27-hydroxylase.
  • CTX prevents cholesterol from being converted into a bile acid called chenodeoxycholic acid. Deposits of cholesterol and cholestanol (a cholesterol derivative) accumulate to cause progressive neurologic decline (eg seizures, ataxia) and early-onset coronary heart disease.
  • Long-term therapy with chenodeoxycholic acid and statins was started; this can prevent the onset of the more severe disease features.

Age-related macular disease: It is now well established that the aetiology of age-related macular disease (the commonest cause of visual disability in developed countries) has a very strong genetic basis. In the future, disease modification – either through treatment or through lifestyle modification - might make disease stratification from molecular analysis a possibility.

Primary open angle glaucoma: Large-scale population studies are helping to clarify the genetic contribution to POAG. In the future it is possible that this will be a valuable adjunct to early diagnosis and screening.

Treatments for rare diseases: Gene replacement therapies represent one of the most exciting opportunities for the treatment of genetic disease. Ophthalmology – specifically in the field of inherited retinal disease – is at the forefront of developments. In 2017, the FDA approved a gene replacement therapy for one form of LCA caused by mutations the in RPE65 gene. Clinical trials are underway for several other inherited retinal disorders including choroideremia and X-linked retinitis pigmentosa.