Using whole-genome sequencing to understand the genetics of cataracts that are present at birth
Research details
- Type of funding: PhD Studentship
- Grant Holder: Prof Graeme Black
- Institute: University of Manchester
- Region: North West
- Start date: October 2011
- End Date: March 2015
- Priority:
- Eye Category:
Overview
Each year in the UK around 200 children are born with cataracts (known as ‘congenital cataract’). It accounts for about 1 in 10 blind children. There is a genetic cause for about 1 in 2 cases of congenital cataract. Faults in more than 100 genes have been linked with the condition.
Usually children with congenital cataract in both eyes need to have lots of tests to try to understand the underlying cause of their cataracts. But most of these test results are normal. It’s time consuming and not very efficient and, even more importantly, it leaves families with no clear answer about why their child has congenital cataract.
Test success
In this project the research team developed a comprehensive genetic test that successfully finds the cause of congenital cataract in around 7 out of 10 cases. This leads to better treatment for some families and much better genetic counselling about what the future might hold.
A lot of this work has been published in scientific journals but the most important results are that there is now a test that’s been adopted by the NHS and the team has also used the test to discover new causes of congenital cataract.
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Scientific summary
The researchers have collected a large cohort of patients with detailed phenotyping and with detailed genomic information.
Molecular analysis:- It is known that genomic analysis can enhance the diagnosis of heterogeneous disease, including those disorders derived from abnormal lens development.
- The team has developed a targeted genomic analysis pipeline which studies 115 genes that are known to cause CC. This successfully identifies genetic mutations in 70-75% of cases. Consequently they now have probably the largest cohort of genotyped patients described to date.
- Functional analysis of genomic loci. Work on families with discovered mutations has allowed the team to define genotype:phenotype correlations, to broaden the understanding of the phenotypic consequences of mutation are different loci and to understand the functional consequences of mutations.
- They have defined a range of mutations in genes which are underdiagnosed but amenable to treatment. This has provided a broad understanding of how diagnosis can impact on treatment and management of patients.
This has resulted in transformational diagnostic testing within the NHS. Identification of the genetic basis of CC and improves diagnosis, and, in the case of syndromic conditions suggests new avenues for treatment. In addition, it informs prognosis, genetic counselling and assists reproductive planning. The team has repeatedly shown that NGS is valuable for diagnosis when offered in an informed multidisciplinary environment. As a consequence Manchester now delivers this through a clinical multidisciplinary team.
The work has resulted in the discovery of novel mechanisms underlying CC and in a broader understanding of the genomic epidemiology of CC. -
Publications
- Gillespie RL, Urquhart J, Lovell SC, Biswas S, Parry NRA, Schorderet DF, et al. Abrogation of HMX1 Function Causes Rare Oculoauricular Syndrome Associated With Congenital Cataract, Anterior Segment Dysgenesis, and Retinal Dystrophy. Investigative Ophthalmology & Visual Science [Internet]. 2015 Feb 5 [cited 2015 Sep 14];56(2):883–91.
- Greenlees R, Mihelec M, Yousoof S, Speidel D, Wu SK, Rinkwitz S, et al. Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization. Hum Mol Genet [Internet]. 2015 Jul 30 [cited 2015 Sep 14];ddv298.
- Gillespie RL, Urquhart J, Anderson B, Williams S, Waller S, Ashworth J, et al. Next-generation Sequencing in the Diagnosis of Metabolic Disease Marked by Pediatric Cataract. Ophthalmology [Internet]. [cited 2015 Sep 14];0(0).
- Gillespie RL, O’Sullivan J, Ashworth J, Bhaskar S, Williams S, Biswas S, et al. Personalized Diagnosis and Management of Congenital Cataract by Next-Generation Sequencing. Ophthalmology. 2014 Jul 29;
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Gillespie RL, Lloyd IC, Black GCM. The Use of Autozygosity Mapping and Next-Generation Sequencing in Understanding Anterior Segment Defects Caused by an Abnormal Development of the Lens. Human Heredity [Internet]. 2014 [cited 2015 Sep 14];77(1-4):118–37. Available from: http://www.karger.com?doi=10.1159/000362599