Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas

Abstract

Neurofibromatosis 2 (NF2) is a severe autosomal dominant disorder that predisposes to multiple tumours of the nervous system. About half of all patients are founders with clinically unaffected parents. The purpose of the present study was to examine the extent to which mosaicism is present in NF2 founders. A total of 233 NF2 founders with bilateral vestibular schwannomas (BVS) were screened by exon scanning. NF2 mutations were detected in the blood samples of 122 patients (52%). In 10 of the 122 cases, the ratio of mutant to normal alleles was obviously less than 1, suggesting mosaicism. Tumour specimens were available from 35 of the 111 subjects in whom no mutation could be detected in blood specimens. Mutational analysis by exon scanning detected typical NF2 mutations in 21 of the 35 tumours. In nine subjects, the alterations found in tumours could be confirmed to be the constitutional mutation based on finding of identical mutations in pathologically and/or anatomically distinct second tumours. In six other subjects with only a single tumour available, allelic loss of the NF2 gene was found in addition to the mutation in each tumour, suggesting that either the mutation or the deletion of the NF2 gene is probably the constitutional genetic alteration. Our results suggest that failure to find constitutional mutations in blood specimen from these 15 patients was not because of the limitation of the applied screening technique, but the lack of the mutations in their leucocytes, best explained by mosaicism. Extrapolating the rate (15/35 = 43%) of mosaicism in these 35 cases to the 111 NF2 founders with no constitutional NF2 mutations found in their blood, we inferred 48 mosaic subjects (111 × 0.429). Adding the 10 mosaic cases detected directly in blood specimens, we estimate the rate of mosaicism to be 24.8% (58/233) in our cohort of 233 NF2 founders with bilateral vestibular schwannomas.

In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2

“…4 Over 50% of patients are familial cases and the other 50% bear de novo mutations. A minimum of 25-33% of these NF2 sporadic cases are mosaic, 5,6 which complicates clinical diagnostics and genetic testing. 7 NF2 patients exhibit a wide mutational spectrum with mutation type frequencies that vary slightly depending on the presence or absence of mosaicism.…”

Empirical development of improved diagnostic criteria for neurofibromatosis 2

“…1,2 The detection rate is approximately 60% in de novo (simplex) cases because 25-30% of such cases are mosaic. 11,12 Some clinical laboratories may use less sensitive methods for detecting pathogenic mutations of the NF2 locus; this would delay the diagnosis of NF2 in a few patients until it can be made on the basis of clinical features alone.…”

“…1,2,25-27 Molecular testing for NF2 mutations has become clinically available, 1,2,26,28,29 and somatic mosaicism has been found to occur in 25-30% of de novo NF2 patients. 11,12 Schwannomatosis has been defined as a distinct clinical entity, 9 excluded from the NF2 locus, 30 and shown to be related to mutations of the SMARCB1 locus in some patients. [31][32][33][34] Most importantly, we have begun to understand the molecular pathogenesis of NF2, 1,[35][36][37] and this is permitting the development of novel therapeutic initiatives.…”

Genetic and clinical characteristics of Korean patients with neurofibromatosis type 2

“…The high prevalence of somatic mosaicism accounts for the difficulty in revealing mutations in sporadic cases of NF2. Thus, identification of the somatic mutations in the affected tumor tissues is warranted [4,24,25].…”

“…NF2 is caused by a mutation in the NF2 gene located at chromosome 22 (22q12.2) and is inherited in an autosomal dominant manner. Approximately 50% of patients have no family history and approximately 25% to 30% of patients show somatic mosaicism [3,4]. Mutations are found in tumor tissues but are often not detectable in lym- …”