Mosaicism in sporadic neurofibromatosis 2 patients

Abstract

More than half of neurofibromatosis 2 (NF2) patients represent de novo mutations which could have occurred at either pre-zygotic or post-zygotic stages. A post-zygotic mutation can result in mosaicism. In four sporadic NF2 patients, we found NF2 mutations in only a portion of corresponding leukocytes. In two other sporadic patients, no mutations were found in leukocytes but constitutional NF2 mutations were suggested by identical mutations in different tumors from each patient. We screened leukocyte DNA from a total of 16 inherited and 91 sporadic NF2 patients, and found NF2 mutations in 13 (81%) of the former and in 46 (51%) of the latter cases. The 30% difference in the rate of detection of mutations ( P = 0.051) might be partially explained by mosaicism in a portion of sporadic NF2 patients who carry the mutations in such a fashion that their leukocytes are unaffected. Among sporadic cases, we found mutations more frequently in patients with severe phenotypes (59%) than in patients with mild phenotypes (23%) (difference of 36%, P = 0.007). Mosaicism might be more common in the latter patient group since small populations of mutation-bearing cells can in some cases result in mild phenotypes and can also lead to difficulties in identifying mutations. No mutations were found in eight patients suspected of having NF2. Mosaicism with an extremely small population of affected cells may explain the incomplete phenotypes in some of these patients and the lack of mutations in their leukocytes. These findings suggest that mosaicism is relatively common in NF2 and may have important implications for diagnosis, prognosis and genetic counseling.

Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring

“…This is higher than previous estimates of 15-20%, 14 15 and corresponds to the difference in the mutation detection rate between people with new mutations (55%) and inherited cases (85%) in this study. Kluwe et al 14 reported direct molecular evidence of mosaicism in six NF2 patients with new mutations by finding mutational hits in blood in four people and in tumour material in two people. The difference in mutation detection rates between people with new mutations and inherited cases was 30%, a difference that they also attributed to mosaicism.…”

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

“…Wallace, personal communication). Review of the body of literature discussed in NF2 Constitutional Alterations section reveals that the majority of constitutional mutations in NF2 patients will be detected by careful exon scanning of blood samples (about 66%) Parry et al, 1996]); however, rates of pickup are clearly affected by disease severity (with low rates in mild patients and nearly 100% rates in very severe patients) and by founder status (with about 30% fewer founders detected than nonfounders) [Kluwe and Mautner, 1998]. In the 50% of patients who are founders, an additional 12% ] to 50% [Mohyuddin et al, 2003] of mutations will be found by exon scanning of tumors.…”

Presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients: A method based on tumor analysis

“…10 Haplotype analysis of the patients, their children, and unaffected spouses as well as allelic loss analysis of the NF2 gene in tumors were performed using five microsatellite markers flanking or within the NF2 gene: CRYB2, D22S275, NF2CA3, D22S268, and D22S430. 12,13 Table 1, the clinical features of the four sporadic NF2 patients fulfill the updated NIH diagnostic criteria for NF2.…”

“…8 Recent findings suggest that 20% to 30% of sporadic NF2 patients may be mosaic. 9,10 In some mosaic cases, the leukocytes of the patients may not bear the mutations and, thus, the mutations cannot be found by screening their blood-DNA. Our previous study demonstrated that, in such cases, analysis of tumors can provide an additional opportunity to find constitutional mutations.…”

“…Our previous study demonstrated that, in such cases, analysis of tumors can provide an additional opportunity to find constitutional mutations. 10 In the present study, we used tumor analysis for presymptomatic diagnosis for eight children of four sporadic NF2 patients in whom no NF2 mutations were found by screening their blood-DNA. …”