Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification

• Published in: Journal of medical genetics Vol. 44; no. 7; pp. 424 - 428
• Main Authors: Evans, D Gareth R, Ramsden, R T, Shenton, A, Gokhale, C, Bowers, N L, Huson, S M, Pichert, G, Wallace, A
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.07.2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Biological and medical sciences; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; FISH; fluorescence in situ hybridisation; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Humans; In Situ Hybridization, Fluorescence; Lymphocytes; Medical genetics; Medical sciences; MLPA; Molecular and cellular biology; Molecular Probe Techniques; Mosaicism; multiple ligation-dependent probe amplification; Mutation; Neurofibromatosis 2 - complications; Neurofibromatosis 2 - genetics; neurofibromatosis type 2; Neurology; Neuroma, Acoustic - etiology; NF2; Nucleic Acid Amplification Techniques; Original; Patients; Pedigree; Polymorphism, Single-Stranded Conformational; Risk Assessment; Tumors; Tumors of the nervous system. Phacomatoses; unilateral vestibular schwannoma; UVS; vestibular schwannoma; Human; Vestibular nerve; Neurofibromatosis II; Nervous system diseases; Multiple; Neurinoma; Risk; Gene amplification; Ligature; Risk factor; Genetics; Mosaicism; Molecular probe; Benign neoplasm; Mutation
• DOI: 10.1136/jmg.2006.047753
• ISSN: 0022-2593; 1468-6244

Background: Neurofibromatosis type 2 (NF2) is almost unique among inherited disorders in the frequency of mosaicism in the first affected generation. However, the implications of this on transmission risks have not been fully elucidated. Methods: The expanded database of 460 families with NF2 and 704 affected individuals was analysed for mosaicism and transmission risks to offspring. Results: 64 mosaic patients, with a projected mosaicism rate of 33% for sporadic classical NF2 with bilateral vestibular schwannoma at presentation and 60% for those presenting unilaterally, were identified. Offspring risks can be radically reduced on the basis of a sensitive mutation analysis of blood DNA including multiple ligation-dependent probe amplification (MLPA, which detects 15% of all mutations), but even MLPA cannot detect high levels of mosaicism. Conclusion: The chances of mosaicism in NF2 and the resultant risks of transmission of the mutation to offspring in a number of different clinical situations have been further delineated. The use of MLPA in this large NF2 series is also reported for the first time.