Background Although 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2.
Methods We performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype–phenotype correlation.
Results Twenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma.
Conclusion We have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with ‘unilateral vestibular schwannoma’ or ‘multiple meningiomas’ presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.
- neuromuscular disease
- clinical genetics
Data availability statement
Data are available on reasonable request. The authors confirm that the data supporting the findings of this study will be shared by request from any qualified investigator.
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Contributors YT analysed and interpreted all clinical data. SM, JM, HN, SM, ST and NS designed the experiments. YT, HH, SD, AO, ST, TO and SM performed the experiments. JY, QW and SM performed the bioinformatic analysis. YT and SM interpreted the results and wrote the manuscript.
Funding This project was supported by a Grant-in-Aid for Scientific Research (B) (No. 17H04301) from the Japan Society for the Promotion of Science to NS, a Grant-in-Aid for Scientific Research (C) (No. 19K09499) from the Japan Society for the Promotion of Science to HN, a Grant-in-Aid for Scientific Research (C) (No. 19K09473) from the Japan Society for the Promotion of Science to SM, a Grant-in-Aid for Research Activity Start-up (No. 19K24023) from the Japan Society for the Promotion of Science to YT, a research grant from Japan Intractable Diseases (Nanbyo) Research Foundation to SM, a research grant from Takeda Science Foundation to SM and a MEXT KAKENHI (Grant No. 221S0002).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.