Purpose:To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).
Methods:Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n=1055), were tested for NF2 variants in lymphocyte DNA and where available tumour DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next generation sequencing.
Results:The rate of proven/presumed mosaicism was 232/1055(22.0%). However, non-mosaic heterozygous pathogenic variants were only identified in 387/1055(36.7%). When mutation detection rates in second generation non-mosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single nucleotide pathogenic NF2 variant.
Conclusion:This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is non-lethal in heterozygote form. Risks to offspring are small and probably correlate with mutation allele frequency detected in blood.