title: RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients.
abstract: BACKGROUND
  Retinoblastoma (Rb) is a childhood cancer of the retina, commonly initiated by biallelic inactivation of the RB1 gene. Knowledge of the presence of a heritable RB1 mutation can help in risk management and reproductive decision making. We report here on RB1 mutation scanning in a unique nationwide cohort of Rb patients from the Netherlands.
  
  
  METHODS
  From the 1173 Rb patients registered in the Dutch National Retinoblastoma Register until January 2013, 529 patients from 433 unrelated families could be included. RB1 mutation scanning was performed with different detection methods, depending on the time period.
  
  
  RESULTS
  Our mutation detection methods revealed RB1 mutations in 92% of bilateral and/or familial Rb patients and in 10% of non-familial unilateral cases. Overall an RB1 germline mutation was detected in 187 (43%) of 433 Rb families, including 33 novel mutations. The distribution of the type of mutation was 37% nonsense, 20% frameshift, 21% splice, 9% large indel, 5% missense, 7% chromosomal deletions and 1% promoter. Ten per cent of patients were mosaic for the RB1 mutation. Six three-generation families with incomplete penetrance RB1 mutations were found. We found evidence that two variants, previously described as pathogenic RB1 mutations, are likely to be neutral variants.
  
  
  CONCLUSIONS
  The frequency of the type of mutations in the RB1 gene in our unbiased national cohort is the same as the mutation spectrum described worldwide. Furthermore, our RB1 mutation detection regimen achieves a high scanning sensitivity.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Dommering
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Berber M
authors.initials: BM
authors.lastname: Mol
authors.affiliation: Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Moll
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Margaret
authors.initials: M
authors.lastname: Burton
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: van der Hout
mesh_terms: D002675:Child, Preschool; D002872:Chromosome Deletion; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D010375:Pedigree; D012175:Retinoblastoma / Q000453:epidemiology / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*
chemical_list: D016160:Retinoblastoma Protein
keywords: Genetic screening/counselling; Retinoblastoma; Retinoblastoma/genetics; mosaicism; mutation