title: Genetic testing in Tunisian families with heritable retinoblastoma using a low cost approach permits accurate risk prediction in relatives and reveals incomplete penetrance in adults.
abstract: Heritable retinoblastoma is caused by oncogenic mutations in the RB1 tumor suppressor gene. Identification of these mutations in patients is important for genetic counseling and clinical management of relatives at risk. In order to lower analytical efforts, we designed a stepwise mutation detection strategy that was adapted to the spectrum of oncogenic RB1 gene mutations. We applied this strategy on 20 unrelated patients with familial and/or de novo bilateral retinoblastoma from Tunisia. In 19 (95%) patients, we detected oncogenic mutations including base substitutions, small length mutations, and large deletions. Further analyses on the origin of the mutations showed mutational mosaicism in one unilaterally affected father of a bilateral proband and incomplete penetrance in two mothers. In a large family with several retinoblastoma patients, the mutation identified in the index patient was also detected in several non-penetrant relatives. RNA analyses showed that this mutation results in an in-frame loss of exon 9. In summary, our strategy can serve as a model for RB1 mutation identification with high analytical sensitivity. Our results point out that genetic testing is needed to reveal or exclude incomplete penetrance specifically in parents of patients with sporadic disease.
authors.affiliation: Laboratoire de Génétique Immunologie et Pathologies Humaines, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Campus universitaire, Tunis 2092, Tunisia. Electronic address: hager.ayajeri@yahoo.fr.
authors.forename: Hajer
authors.initials: H
authors.lastname: Ayari Jeridi
authors.affiliation: Institut Hédi Rais d'Ophtalmologie de Tunis, Tunisia.
authors.forename: Hédi
authors.initials: H
authors.lastname: Bouguila
authors.affiliation: Eye Cancer Research Group, Institut für Humangenetik, Universitätsklinikum Essen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Ansperger-Rescher
authors.affiliation: Laboratoire de Génétique Immunologie et Pathologies Humaines, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Campus universitaire, Tunis 2092, Tunisia.
authors.forename: Olfa
authors.initials: O
authors.lastname: Baroudi
authors.affiliation: Laboratoire de Génétique Immunologie et Pathologies Humaines, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Campus universitaire, Tunis 2092, Tunisia.
authors.forename: Imen
authors.initials: I
authors.lastname: Mdimegh
authors.affiliation: Laboratoire de Génétique Immunologie et Pathologies Humaines, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Campus universitaire, Tunis 2092, Tunisia.
authors.forename: Ines
authors.initials: I
authors.lastname: Omran
authors.affiliation: Laboratoire de Génétique Immunologie et Pathologies Humaines, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Campus universitaire, Tunis 2092, Tunisia.
authors.forename: Khaoula
authors.initials: K
authors.lastname: Charradi
authors.affiliation: Laboratoire de Génétique Immunologie et Pathologies Humaines, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Campus universitaire, Tunis 2092, Tunisia.
authors.forename: Hssan
authors.initials: H
authors.lastname: Bouzayene
authors.affiliation: Laboratoire de Génétique Immunologie et Pathologies Humaines, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Campus universitaire, Tunis 2092, Tunisia.
authors.forename: Amel
authors.initials: A
authors.lastname: Benammar-Elgaaïed
authors.affiliation: Eye Cancer Research Group, Institut für Humangenetik, Universitätsklinikum Essen, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Lohmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005091:Exons; D005190:Family; D005260:Female; D016161:Genes, Retinoblastoma / Q000235:genetics*; D005820:Genetic Testing / Q000191:economics* / Q000379:methods; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D019572:Retinal Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D012175:Retinoblastoma / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014416:Tunisia / Q000453:epidemiology; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D016160:Retinoblastoma Protein
keywords: RB1 gene; genetic testing; heritable; penetrance; retinoblastoma