Your weekly snapshot of clinically actionable genes from the ACMG Secondary Findings List.

Clinical Phenotype Summary: 
The NF2 gene (NM_000268.3) is located on chromosome 22q12.2, encodes the merlin protein, and contains 16 coding exons. Pathogenic variants in this gene have been detected in individuals with NF2-related schwannomatosis (SWN), which is inherited in an autosomal dominant fashion. 

NF2-related SWN is characterized by:

• Increased risk of:
  • Bilateral vestibular schwannomas (present in over 90% of individuals) 
  • Schwannomas of other cranial nerves (in 24-51%)
  • Intracranial meningiomas (in 45-58%)
  • Spinal tumors including meningiomas, schwannomas, ependymomas, and rarely astrocytomas (combined 63-90%) 
• In addition to these lesions, individuals with NF2-related SWN can also develop ophthalmological manifestations such as:
  • Juvenile subcapsular or cortical cataract
  • Retinal hamartomas
  • Epiretinal membrane
• Variable expressivity is observed, although intrafamilial variability is much lower than interfamilial variability, and can be related to mosaicism and/or genotype-phenotype correlations. Loss of function has been reported as the mechanism of disease for NF2-related SWN.

Unique Considerations:

• Approximately 50% of all NF2 pathogenic variants are de novo events, of which up to 30% are mosaic.
• Large deletions in NF2 have been associated with a mild phenotype, while truncating and frameshift pathogenic alterations have been associated with a more severe phenotype.

Clinical Resources: 

Understanding Your Positive NF2 Genetic Test Result

Citations: 

• Baser ME et al. Journal of Medical Genetics. 2005 42(7):540-6. PMID15994874
• Petrilli AM,Fernández-Valle C. Oncogene 2016 Feb; 35(5):537-48. PMID25893302
• Batista PB  et al. Arquivos de neuro-psiquiatria 2015 Jun; 73(6):531-43. PMID26083891
• Plotkin SR  et al. Genetics in medicine : official journal of the American College of Medical Genetics 2022 Sep; 24(9):1967-1977. PMID35674741
• Asthagiri AR  et al. Lancet (London, England) 2009 Jun; 373(9679):1974-86. PMID19476995
• Evans DG et al. Journal of medical genetics 1998 Jun; 35(6):450-5. PMID9643284 
• Evans DG et al. Genetics in medicine : official journal of the American College of Medical Genetics 2019 07; 21(7):1525-1533.PMID 30523344.
• Evans DG. GeneReviews®. 1998 October 14 [Updated 2018 March 15]. PMID20301380.
• Baser ME et al. Journal of medical genetics 2005 Jul; 42(7):540-6. PMID15994874.
• Baser ME et al. American journal of human genetics 2004 Aug; 75(2):231-9. PMID15190457.
• Baser ME et al. American journal of human genetics 2002 Oct; 71(4):715-23. PMID12235555.
• Ruggieri M et al. Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale 2016 Oct; 36(5):345-367. PMID27958595.
• Baser ME et al. Genetics in medicine : official journal of the American College of Medical Genetics 2011 Jun; 13(6):576-81. PMID21451418.
• Baser ME et al. Neurology 2002 Dec; 59(11):1759-65. PMID12473765.
• Perry A et al. Journal of neuropathology and experimental neurology 2001 Oct; 60(10):994-1003. PMID11589430.
• Moyhuddin A et al. Journal of medical genetics 2003 Jun; 40(6):459-63. PMID12807969.
• Kluwe L et al. Journal of medical genetics 2003 Feb; 40(2):109-14. PMID12566519.
• Evans DG et al. Journal of medical genetics 2007 Jul; 44(7):424-8. PMID17307835.
• Evans DG et al. Archives of disease in childhood 1999 Dec; 81(6):496-9. PMID10569966.
• Evans DG et al. The Quarterly journal of medicine 1992 Aug; 84(304):603-18. PMID1484939
• Dow G et al. Journal of neurosurgery. Spine 2005 May; 2(5):574-9. PMID15945431.
• Zhang et al. Discovery medicine 2014 Dec; 18(101):301-11. PMID25549701.

Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early.

To learn more about the ACMG Secondary Findings list, click here.

To read all previous Gene Scene emails, click here.