NF2 – NF2-related Schwannomatosis

Neurofibromatosis 2 (NF2)-related schwannomatosis is an autosomal dominant tumor predisposition syndrome characterized by bilateral vestibular schwannomas, meningiomas, ependymomas, and other peripheral nerve sheath tumors. Germline heterozygous variants in the NF2 gene (HGNC:7773) disrupt merlin, a cytoskeletal–membrane linker with tumor-suppressor function. We assign a ClinGen clinical validity of Definitive for the NF2–NF2-related schwannomatosis association based on multiple families, multigenerational segregation, and concordant functional studies.

Autosomal dominant inheritance is supported by segregation of a C-terminal missense variant, c.1604T>C (p.Leu535Pro), in eight family members (five affected and three obligate carriers) across two generations with late-onset hearing loss and vestibular schwannomas ([PMID:7666400]). Penetrance approaches 100% by sixth decade, with population incidence ∼1 in 25 000 live births ([PMID:26539318]).

Over 300 distinct NF2 pathogenic variants have been reported, predominantly protein-truncating changes (nonsense, frameshift, splice-site), with a minority of missense alleles. Recurrent LoF variants like c.784C>T (p.Arg262Ter) illustrate hotspot C→T transitions at CpG sites. ClinGen genetic evidence is scored Strong: extensive case series, multigenerational segregation, and a broad spectrum of variant classes documented in >1 000 probands ([PMID:9643284]).

Mechanistically, loss of merlin abrogates its FERM-domain-mediated linkage to the actin cytoskeleton. Functional assays demonstrate that merlin interacts with βII-spectrin, and that missense and truncating mutations disrupt this interaction, impair cell adhesion and contact-inhibition, and activate Rac/Pak signaling ([PMID:9537418]). Animal and cellular models confirm merlin’s tumor-suppressor role in Schwann cells.

Somatic and gonosomal mosaicism are common, with targeted deep sequencing revealing mosaic NF2 variants in ~38% of sporadic cases and low-level alleles in blood and tumor tissues, refining diagnostic sensitivity ([PMID:33067351]). Mosaicism explains variable expression and reduced transmission risk in de novo presentations.

Integrated genetic and functional data establish NF2 haploinsufficiency and merlin inactivation as the basis for schwannomatosis, guiding predictive testing, surveillance, and targeted therapies. Key take-home: NF2 genetic testing and deep sequencing for mosaicism are clinically essential for accurate diagnosis and management in families with vestibular schwannomas.

References

• Journal of medical genetics • 1995 • Diagnostic issues in a family with late onset type 2 neurofibromatosis. PMID:7666400
• Surgical neurology international • 2015 • Neurofibromatosis type 2 patient presenting with medulloblastoma. PMID:26539318
• Journal of medical genetics • 1998 • Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. PMID:9643284
• Nature genetics • 1998 • Neurofibromatosis 2 tumour suppressor schwannomin interacts with betaII-spectrin. PMID:9537418
• Journal of medical genetics • 2021 • Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2. PMID:33067351

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