NF2-related schwannomatosis is a tumor predisposition syndrome caused by diverse NF2 alterations, including truncating variants, copy-number changes, and non-truncating variants such as in-frame indels. Molecular and clinical correlations of these variant types remain incompletely defined, particularly for rare deletions. We present two distinct cases highlighting NF2 inactivation spectrum. Case 1 describes a 62-year-old man with a jugular foramen schwannoma harboring a novel somatic NF2 in-frame deletion (c. 713₇33del, p. Ala238Tyr244del) resulting in complete Merlin expression loss. Structural modeling predicted FERM-C subdomain destabilization; copy-neutral loss of heterozygosity confirmed biallelic inactivation. Case 2 describes a 55-year-old woman with early-onset bilateral vestibular schwannomas caused by a germline whole-gene NF2 deletion, with additional somatic mutations (splice-site and frameshift) inactivating the second allele. Pedigree analysis demonstrated paternal inheritance, underscoring the relevance of genetic counseling. Both tumors displayed classical schwannoma histology with absent Merlin staining, confirming functional NF2 loss. These cases emphasize the necessity of comprehensive molecular testing-including targeted sequencing, whole-genome sequencing, and multiplex ligation-dependent probe amplification-to detect nucleotide-level and large-scale NF2 alterations; moreover, they expand the NF2 mutation spectrum, illustrate pathogenic mechanisms across germline and somatic contexts, and provide clinically actionable insights for Merlin-deficient tumors.
Okazaki et al. (Wed,) studied this question.