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Two novel germline mutations of the retinoblastoma gene (RB1) that show incomplete penetrance, one splice site and one missense
  3. M BURTON*,
  4. E VERLIND*,
  5. A C MOLL,
  6. S M IMHOF,
  7. C H C M BUYS*
  1. * Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, NL-9713 AW Groningen, The Netherlands
  2. Department of Ophthalmology, Free University Hospital, De Boelelaan 1117, NL-1081 HV Amsterdam, The Netherlands
  1. Dr Scheffer, h.scheffer{at}

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Editor—Retinoblastoma (RB) is an intraocular eye tumour with a newborn incidence of 1 in 15 000-25 000.1Of all retinoblastoma patients, 10-15% represent familial cases with an autosomal dominantly inherited predisposition for tumour development. On the basis of epidemiological data, Knudson2 hypothesised that retinoblastoma is a cancer caused by two mutational events. DNA analysis by Cavenee et al 3confirmed this hypothesis. In the familial form, the first mutation is inherited via a germ cell and is, therefore, present in all somatic cells. The second mutation occurs in a somatic cell. In the non-hereditary form, both mutations occur in one and the same somatic cell. From this “two hit” model, it can be predicted that statistically a fraction of carriers of a mutation predisposing to retinoblastoma will never become affected. Indeed, in approximately 10% of families with hereditary retinoblastoma, obligate asymptomatic carriers of a mutant allele of the retinoblastoma gene (RB1) can be identified.1Asymptomatic carriers of a predisposing RB1mutation are, however, not randomly distributed over families with hereditary retinoblastoma. Some families have been identified in which the majority of mutation carriers are either unaffected or only unilaterally affected. In a small number (fewer than 2%) of mutation carriers, clinically benign retinal lesions, or “retinomas”, occur.4 Most likely, retinoma arises when the second mutation occurs in an almost terminally differentiated retinal cell.5 Patients with retinoma can only be detected on ophthalmological inspection. They may, therefore, usually pass for being unaffected, but transmit the mutation predisposing to retinoblastoma to their offspring. Thus, they resemble true asymptomatic carriers of an RB1 germline mutation. DNA analysis of markers within and flanking theRB1 gene allows the identification within retinoblastoma families of healthy subjects in whom the mutation is non-penetrant.6 It has been shown that the non-random …

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