Genetic Screening for Retinoblastoma: Where Do We Stand?

Although complex, costly, and sometimes unpredictable, testing appropriate candidates can be invaluable.

Genetic Screening for Retinoblastoma: Where Do We Stand?
Although complex, costly, and sometimes unpredictable, testing appropriate candidates can be invaluable.

By William J. Wirostko, MD

Genetic testing for retinoblastoma formally began in 1986, when the RB1 tumor suppressor gene was identified. Located on chromosome 13Q, it is a rather large gene with 180,000 bases and 27 exons. In screening, we look for any of the more than 368 known mutations.

The goal of genetic screening is to identify individuals who have or are inheriting an abnormal RB1 allele, primarily because these people are halfway on their route to tumor formation. The information also can help guide our care of their siblings, and it helps parents with family planning.

Today, overall sensitivity is about 90%, but we're still facing some significant limitations. The gene is large, and mosaicism is a testing factor.


Mosaicism is the concept that an individual's chromosome makeup is not homogeneous. For instance, the retinal and the germline cells may contain the inherited mutation, but the peripheral blood cells may not, due to a mutational event during embryogenesis. This confounds genetic testing. The mutation in the tumor, the peripheral blood and the patient's offspring don't always follow the Mendelian inheritance that we understand.

A 1998 study by Sippel and colleagues1 suggested that mosaicism may be present in up to 10% of cases. For example, in some, the peripheral blood was negative for a mutation identified in a patient's tumor, but offspring had retinoblastoma. This is important when considering whether to pursue genetic screening and how we interpret the results. It's also essential to discuss mosaicism with patients in genetic counseling.

Mosaicism, which may be present in 10% of cases, severely confounds genetic counseling.


The value of screening depends on how suspicious we are that a family is harboring the germline mutation, for example:

 A family with multiple cases. Here, we know a germline mutation exists, and genetic screening will give us a high chance of identifying it. With a tumor to test, the odds are even better. Mosaicism is not an issue because it occurs only in the person who has the spontaneous mutation; no descendant should be mosaic. Test results can dramatically influence evaluation, management, additional family screening and family planning.

 Embryos in a family with two cases. In an exciting recent development, physicians diagnosed an embryonic mutation before implantation. They implanted only embryos that did not have the mutation on day 5. In one family, the father and the daughter had bilateral retinoblastoma. Two subsequent offspring were tested before implantation, and they're doing well so far.

 A child with multifocal disease but no family history. For this patient, genetic screening is valuable, and the tumor is helpful for testing. The child is likely harboring the germline mutation. However, in this situation, mosaicism is a possibility, and we must interpret any false negative with caution.

 A child with unifocal disease and no family history. This child benefits least from genetic screening, but the benefits are still unclear. Only 12% of children like this one harbor the systemic mutation, so negative results are high. Because mosaicism is possible, the result has less of an effect on management.


The complexity of testing such a large gene and the unpredictability of mosaicism are limitations to genetic screening, but we still can achieve several of our goals. The results are helping guide patient care and family planning for many patients, particularly those we've identified as the best candidates for testing.

Dr. Wirostko is assistant professor of ophthalmology at the Medical College of Wisconsin in Milwaukee.


1. Sippel KC, Fraioli RE, Smith GD, et al. Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet. 1998:62:610-619.

2. Xu K, Rosenwaks Z, Beaverson K, et al. Preimplantation genetic diagnosis for retinoblastoma: the first reported liveborn. Am J Ophthalmol. 2004;137:18-23.