Schwannomatosis-associated NF2 variants are inherited in an autosomal dominant manner. They are normally loss-of-function variants and pathogenic variants have been identified in every exon, except the mutually exclusive 3’ exons (16 and 17). Somatic loss of the wildtype allele results in tumour development.
Genotype-phenotype correlations have shown that truncating variants (e.g. nonsense or frameshift) cause a more severe clinical phenotype than non-truncating variants (e.g. missense or splice-site) or large deletions.
Sequencing and copy number testing is recommended to confirm a diagnosis. However, NF2-related schwannomatosis has a high frequency of mosaic disease, which can be missed on standard testing. This can be confirmed by identification of identical mutations in two anatomically distinct tumour. High read-depth sequencing can be used to increase the likelihood of identifying mosaic variants when more than one tumour is not available.
NF2