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Retinoblastoma Genetic Screening

The Barts Health Retinoblastoma Genetic Screening Unit is one of only two genetics centres for retinoblastoma (a form of eye cancer) in the UK. We provide a genetics service for patients and their relatives, performing molecular genetic tests for predisposition to retinoblastoma.

We work closely with our colleagues in the retinoblastoma service, which is a designated provider of retinoblastoma care in England and Wales.

This information is for physicians, ophthalmologists and oncologists offering information and guidance about the services of the Retinoblastoma Genetic Screening Unit.

The Unit participates in the external quality assessment scheme organised by the European Molecular Genetics Quality Network (EMQN), is fully accredited by Clinical Pathology Accreditation (UK) Ltd (CPA) and is a diagnostic member of the UK Genetic Testing Network (UKGTN).

Our user manual contains all the information needed for genetic counsellors and physicians to submit specimens to the Unit. Please ensure you have the parent/guardian's consent before making a request.

The disease

Retinoblastoma (OMIM reference number 180200) is a rare form of eye cancer that occurs in children (it makes up 3% of all childhood cancers) that develops in the cells of the retina, the light sensitive lining of the eye. It often occurs before the age of five with an incidence of approximately one in every 20,000 births.

The majority of retinoblastoma patients (85%) have no family history of the disease. In 15% of cases, however, a blood relative has also had retinoblastoma.

In about two thirds of children only one eye is affected (known as unilateral retinoblastoma) while the remainder develop tumours in both eyes (known as bilateral retinoblastoma). When retinoblastoma is passed from parent to child, the disease is often bilateral. The mean age of diagnosis of unilateral retinoblastoma is 28 months while that for bilateral retinoblastoma is eight months. With early detection and modern medical care, the survival rate for children with retinoblastoma is more than 95%. Ongoing research and new treatment developments are saving an increasing number of affected eyes from enucleation (removal), and are maximizing the visual outcome and quality of life for each affected child.

Genetic testing for this disease allows the monitoring of children known to carry a predisposing mutation, so that tumours can be detected and treated promptly. Conversely, it excludes children who are not carriers from frequent examinations. Additionally, the knowledge gained can be used by affected families in family planning, with pre-natal testing of carrier status being made possible. In some cases, preimplantation diagnosis may also be possible. Adults who are aware of being carriers of disease susceptibility should also be vigilant in later life as they are prone to other types of cancer (e.g. lung, skin, breast and bone).

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The genetics

The retinoblastoma susceptibility gene, RB1 (Genbank sequence accession number L11910.1; NCBI RefSeq NM_000321.2), is located on chromosome 13q14 and is a tumour suppressor gene. Mutations in both copies (alleles) of the RB1 gene are necessary for the development of retinoblastoma. 

In about 50% of affected children, both mutations occur in a single retinal cell by chance and cannot be passed to offspring. These children have unilateral (one eye), unifocal (one tumour) disease. In the remaining patients one ‘predisposing’ mutation is present in germ line cells (sperm or ova) and can be transmitted to offspring. This is genetic/hereditary retinoblastoma which generally affects both eyes (bilateral disease) when inherited. Somatic and/or germ line mosaicism, where some but not all cells contain the predisposing mutation, is observed in some founders of new mutation lineages. 

In the sporadic (no family history) unilateral form of retinoblastoma, it is not possible to know without genetic testing whether the disease will be heritable unless the patient has affected offspring. It is estimated that around 15% of such sporadic cases do carry germ line mutations. Early identification of these cases requires genetic testing which is most efficiently done using tumour tissue from an enucleated eye.

The spectrum of predisposing RB1 gene mutations includes large structural changes (about 10-20%) some of which are also detectable by cytogenetic analysis. Other changes include single base substitutions (about 50-60% of mutations) and small insertions/deletions (about 30%). 60-70% of tumours exhibit loss of heterozygosity (loss of one copy/allele) with a mutation in the remaining copy. Finally, hypermethylation at the RB1 gene promoter, which inhibits the levels of retinoblastoma protein made by the cell rather than its function, is observed in around 10% of tumours.

Variable penetrance (the probability that a specific mutation will lead to cancer development) and expressivity (the number of tumours occurring) is a feature of retinoblastoma. Much of this variation is due to the different types of RB1 mutation. Mutations that result in premature termination (truncated protein) are most often associated with almost complete penetrance and bilateral retinoblastoma. However, milder disease with incomplete penetrance and reduced expressivity is usually found in families with missense mutations, some splice site changes, small in-frame deletions and promoter region mutations.

The risk of other members of the family being affected depends upon whether or not the affected child (proband) has a germline RB1 mutation. 

Bilateral retinoblastoma is considered to be hereditary. Whether a sporadic unilateral retinoblastoma is heritable can only be known by identification of both RB1 mutations in the retinoblastoma tumour. A blood sample must then be examined for the same pair of mutations. Finding one of the candidate mutations in blood indicates heritable retinoblastoma. The absence of RB1 mutations in blood suggests non-heritable retinoblastoma, although a small risk of mosaicism remains where the mutation is present in too few blood cells to be reliably detected. 

Once a heritable mutation is identified, molecular testing can determine which members of a family are at risk of developing retinoblastoma. Children who do not carry the family's RB1 mutation are not at increased risk. Children who do carry the mutation can be examined frequently for tumours and treated early if any are detected. The children of germ line mutation carriers have a 50% risk of inheriting the parent’s RB1 mutation (lower if the parent is mosaic) and developing retinoblastoma. However, in certain families with incompletely penetrant RB1 mutations the risk of developing retinoblastoma is lower. 

In cases where a mutation can not be identified, linkage analysis using polymorphic markers within and adjacent to the RB1 gene can be used (exclusion testing) to modify the risk of other family members. 

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Detection of retinoblastoma

Our sensitivity for detection of unknown mutations is shown below, based on over 500 families analysed between April 2005 to March 2013.

In familial/bilateral cases and tumours, our detection rate is >95%.  In unilateral sporadic cases the expected germline mutation figure is 15-20%.  Our unilateral sporadic tumour data shows that one of the tumour mutations is present in the blood of 18% of these patients (24 mutations in 172 unilateral sporadic bloods represents 77% of this expected figure).

RB sample type Tested Mutation found Sensitivity
Familial and bilateral sporadic blood 165 157 95.2%
Tumour 179 271/281 expected mutations 96.4%
Unilateral sporadic blood 172 24 14%

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