Next-generation genetic test points the way to personalised care for children born with cataracts
A team led by Professor Graeme Black at Manchester Centre for Genomic Medicine in St Mary’s Hospital, Manchester has found a fast, precise and cost-effective way to help ensure that children with congenital cataracts get the right diagnosis.
Treatment and advice for the families affected by congenital cataracts can vary widely due to the difficulty of accurately identifying the cause. However, by using next-generation DNA sequencing, which allows a large number of genes to be screened in one test, the researchers were able to assign the problem to specific genes, making earlier and more appropriate care possible.
A cataract is when the lens in the eye – the clear part that focuses light – becomes cloudy, causing blurred or hazy vision. Congenital cataracts, which account for about 10% of childhood blindness, are particularly important because they can mean that a child’s visual development is disrupted, leading to significant sight loss and blindness. They can also be the first sign of a number of more complex conditions, involving other parts of the body.
Until now the cause of an individual child’s congenital cataracts has been determined via a complex series of clinical tests, as well as genetic testing for the most likely genetic fault, based on family history. This process can delay diagnosis and treatment and makes it hard to advise the family on risk to future children. It is also costly to the NHS. More than 110 different cataract-causing genes have already been identified and not enough is known about the relationship between a particular genetic fault and an individual’s clinical symptoms.
What did the researchers do?
In this study, which was funded by the charity Fight for Sight, PhD student Rachel Gillespie used next-generation DNA sequencing to scan each participant for the full range of genes known to be involved in cataracts and matched that information with their individual symptoms. She was able to show that this method of scanning many genes in parallel is highly accurate and can, in some cases, lead to a radically different diagnosis than initially indicated. Prior to this, conventional screening methods were used which involved the consecutive testing of each gene separately to determine the precise genetic cause, which is a time-consuming and costly process.
DNA from thirty-six individuals with congenital cataracts was chosen for the study. Existing medical records indicated that 16 of the patients had cataracts as part of a wider condition (‘syndromic’ congenital cataracts), while 20 had cataracts alone (‘non-syndromic’ congenital cataracts’).
Results from the study
Results, published in the journal Ophthalmology, showed that next-generation DNA sequencing was able to pinpoint a precise genetic cause in 75% of cases overall. A likely genetic fault was found in 85% of patients in the non-syndromic group, and in 63% of the syndromic group.
One patient, who had been provisionally diagnosed with a particular form of syndromic congenital cataract based on family history, was discovered to have been born with a new genetic fault, not previously seen in the family. This dramatically altered the genetic counselling given both to the patient and her parents. Another patient was found to have a disorder that progressively affects development, resulting in severe epilepsy and wheelchair-use by late childhood. It is unlikely that this child would have been diagnosed so early without the new test.
“Next-generation DNA sequencing will transform research into congenital cataracts,” said Prof Black. “We will be able to gain a better understanding of how specific genetic mutations affect proteins in the lens and of the cataract-forming biomechanical pathways. It could also lead to insights into the pathology of the more common age-related cataracts and to the development of novel gene therapies.”
“This study demonstrates the clinical usefulness of this test, and it is great that this test is now available on the NHS by referral to Manchester Centre for Genomic Medicine,” said Dr Dolores M Conroy, Director of Research at Fight for Sight. “It will enable better, individually focussed care pathways and more accurate genetic counselling. Ultimately, this new diagnostic test will improve outcomes for children born with cataracts.”