The first report indicating a relationship of the NF2 gene with autosomal dominant Neurofibromatosis type 2 was reported by Rouleau et al., 1993 (PMID: 8379998), albeit neurofibromatosis (subtypes not defined) was a widely recognized pathologic clinical entity in the late 19th century (Ahn et al., 1994; PMID: 25996397). Neurofibromatosis type 2 is characterized by the formation of benign bilateral or unilateral tumors (schwannomas, meningiomas, gliomas, and/or neurofibromas) in the central nervous, most commonly on the eighth cranial nerve (reviewed on www.ctf.org). Current evidence suggests a prevalence of Neurofibromatosis type 2 of 1 in 25,000 (www.ctf.org). Numerous variants have been reported, in both ClinVar and in LOVD (https://databases.lovd.nl/shared/genes/NF2). Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 20 years, therefore a significant amount of case-level data, segregation data, and experimental data is available and the maximum score for genetic evidence (12 points) and experimental evidence (6 points) has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. In particular, earlier compelling evidence suggestive of the gene-disease relationship, such as linkage data, may not be reflected in the current curation.
The mechanism for the gene-disease relationship is protein loss of function, as the NF2 protein product, termed Merlin or Schwannomin, is a tumor suppressor protein (Trofatter et al., 1993; PMID: 8453669). NF2 tumor suppressor function is regulated by the protein confirmation, with the closed form acting as the active tumor suppressor form (reviewed in Cooper and Giancotti, 2014 PMID:24726726).
NF2 has been associated with multiple disease entities and/or phenotypes, including: (1) Meningioma, NF2-related, somatic (MIM: 607174) (2) Schwannomatosis, somatic
Of note, these other phenotypes are noted as somatic, and therefore are not represented/ counted in this gene-disease relationship, and will be assessed separately.
In summary, NF2 is DEFINITIVELY associated with autosomal dominant Neurofibromatosis Type 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on February 27, 2019.
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