Retinoblastoma (RB) is an intraocular malignancy of the developing retina associated with germline and/or somatic mutations of the RB1 tumor suppressor gene. RB is a childhood cancer; typically presenting in the first 5 years of life and occurring at a frequency of approximately 1 in 15,000-20,000 live births.^1,3 The most common sign of RB is a visible whiteness in the pupil called leukocoria or "cat's eye reflex".² Other signs and symptoms of retinoblastoma include strabismus, irritation, redness, persistent eye pain and vision impairment in the affected eye. Approximately 60% of RB is unilateral (affecting a single eye), while the other 40% of cases are bilateral (affecting both eyes).³ RB occurs in hereditary and non-hereditary forms, with all bilateral RB and some unilateral RB cases being hereditary.

Children with hereditary RB harbor a germline RB1 mutation due to parental transmission or, more commonly, a de novo event. Hereditary RB is an autosomal dominant, highly penetrant cancer predisposition syndrome characterized by an increased risk of RB and a spectrum of secondary, non-ocular malignancies, most commonly osteosarcoma, pinealoma and melanoma.^4,5 In addition, germline RB1 mutations have been shown to confer susceptibility to radiation-induced malignancies.^4,6

The RB1 gene (NM_000321.2) comprises 27 exons, spanning approximately 178kb of genomic DNA, and maps to chromosome 13q14.2.  It encodes a 928 amino acid nuclear phosphoprotein pRB, which functions as a negative regulator of the cell cycle and cell proliferation. To date, 673 RB1 mutations have been reported in the Human Gene Mutation Database (HGMD), the majority of which are small deletions, missense/nonsense and splicing.