ORIGINAL ARTICLE

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

D Gareth R Evans¹, R T Ramsden¹, A Shenton¹, C Gokhale¹, N L Bowers¹, S M Huson¹, G Pichert², A Wallace¹

¹ Academic Unit of Medical Genetics and Regional Genetics Service, St Mary’s Hospital, Manchester, UK
² Genetics Centre, Guys Hospital, London, UK

Correspondence to:
Professor D G R Evans
Department of Medical Genetics, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, UK;gareth.evans{at}cmmc.nhs.uk

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.

Abbreviations: FISH, fluorescence in situ hybridisation; MLPA, multiple ligation-dependent probe amplification; NF2, neurofibromatosis type 2; UVS, unilateral vestibular schwannoma; VS, vestibular schwannoma

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