Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2

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.

Automated summary

Improved diagnostic rate of mosaic NF2 was achieved by targeted deep sequencing of DNA from multiple tissues. Patients with mosaic NF2 showed significant differences in phenotype compared to those with NF2 germline variant, particularly in tumor growth rate and hearing outcome. Schwannoma behavior correlated with the extent of VAF in normal tissues carrying NF2 variant, unlike meningioma.