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Genetic Counseling

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Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Mode of Inheritance

Neurofibromatosis 2 (NF2) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 50% of individuals with NF2 have an affected parent, and 50% have NF2 as the result of a de novo mutation. However, 25% to 33% of individuals who are simplex cases (i.e., individuals with no family history of NF2) are mosaic for an NF2 mutation [Kluwe et al 2003, Moyhuddin et al 2003, Evans et al 2007b].

  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a clinical history and, if any suspicion of NF2 exists, an MRI scan. The possibility that a parent has NF2 can be excluded if his/her offspring is shown to be mosaic, but absence of a mutation detected in the child does not eliminate the possibility of mosaicism in the parent. Because the age of onset of symptoms is consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.

  • If a parent of the proband is affected, the risk to the sibs is 50%.

  • If neither parent of an individual with NF2 is symptomatic, the risk to the sibs of the affected individual is low because the age of onset of symptoms is relatively uniform within families. However, a single case of germline mosaicism in a clinically normal parent has been reported. In addition, somatic mosaicism (which may include germline mosaicism) is found in 25%-33% of individuals with NF2 who are simplex cases.

Offspring of a proband. Each child of an individual with NF2 has up to a 50% chance of inheriting the mutation:

  • If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the mutation.

  • If the proband is the only affected individual in the family, two possibilities exist:

    • The proband may have somatic mosaicism for the disease-causing mutation. Offspring of an individual who is mosaic may have less than a 50% risk of inheriting the disease-causing mutation.

    • The proband may have a de novo germline mutation (i.e., present in the egg or sperm at the time of conception). Each offspring of an individual with a de novo germline mutation has a 50% chance of inheriting the mutation.

  • Persons with somatic mosaicism and bilateral vestibular tumors have less than a 50% chance of having an affected child [Evans et al 1998b]. If the mutation is detected in DNA from multiple tumors, but not in DNA from leukocytes, the risk to offspring is probably less than 5%.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members may be at risk, depending on the family structure.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Considerations in families with an apparent de novo mutation. When the parents of a proband with an autosomal dominant condition are unaffected, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic family members. Consideration of molecular genetic testing of at-risk family members during childhood is appropriate for surveillance (see Surveillance). Molecular genetic testing used in early identification of at-risk family members may be either mutation analysis or linkage analysis. Mutation analysis can be used for testing of at-risk relatives only if a disease-causing mutation has been identified in an affected family member. Linkage analysis is the preferred method of testing in families with more than one affected family member if the family-specific mutation has not been identified.

Because early detection of at-risk individuals affects medical management, testing of at-risk asymptomatic individuals younger than age 18 years is beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the altered gene. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See Image testing.jpg for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis of pregnancies at 50% risk for NF2 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see Image testing.jpg.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetics

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Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Neurofibromatosis 2: Genes and Databases
Gene Symbol Chromosomal Locus Protein Name HGMD
NF2 22q12.2 Merlin NF2
Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) linked to, click here.
Table B. OMIM Entries for Neurofibromatosis 2 (View All in OMIM)
101000 NEUROFIBROMATOSIS, TYPE II; NF2
607379 NEUROFIBROMIN 2; NF2

Normal allelic variants. NF2 spans 110 kilobases and comprises 16 constitutive exons and one alternatively spliced exon. NF2 is widely expressed, producing mRNAs in three different lengths of approximately 7, 4.4, and 2.6 kb. No frequent normal allelic variants, even in codon wobble positions, have been reported in NF2.

Pathologic allelic variants. At least 200 different mutations in NF2, the majority of which are point mutations, have been described [Legoix et al 2000, Baser 2006].

A wide variety of mutations have been identified in all NF2 exons, except for the alternatively spliced exons 16 and 17.

  • Ninety percent of point mutations are predicted to truncate the protein by introduction of a premature stop codon, a frameshift with premature termination, or a splicing alteration, supporting the view that loss of the protein's normal function is necessary for the development of tumors. C to T transitions in CGA codons causing nonsense mutations are an especially frequent occurrence.

  • Fewer than 10% of detected mutations involve in-frame deletions and missense mutations, which may indicate that alteration of particular functional domains can abolish the NF2 tumor suppressor activity [Baser et al 2006].

Normal gene product. The NF2 protein product has been named "merlin" (for moezin-ezrin-radixin-like protein) because of the high homology to the 4.1 family of cytoskeletal associated proteins. Alternatively, the name schwannomin has been proposed in recognition of its role in preventing schwannoma formation.

All 4.1 family members have a homologous domain of approximately 270 amino acids at the N terminus. In the NF2 protein and its close relatives, this domain is followed by a long alpha helical segment and a charged C terminal domain. Protein 4.1, the best studied member of the family, plays a critical role in maintaining membrane stability and cell shape in the erythrocyte by connecting integral membrane proteins, glycophorin, and the anion channel to the spectrin-actin lattice of the cytoskeleton. Protein 4.1 is the only other family member in which disease-causing mutations are known (hereditary elliptocytosis).

Two major alternative forms of the NF2 protein product exist. Isoform 1 is a protein of 595 amino acids produced from exons 1 through 15 and exon 17. Presence of the alternatively spliced exon 16 alters the C terminus of the protein, replacing 16 amino acids with 11 novel residues in isoform 2. Additional alternative splices predicting other minor species have also been described.

Although the complete function of the NF2 protein remains elusive, recent studies suggest that “merlin” may coordinate the processes of growth-factor receptor signaling and cell adhesion. Varying use of this organizing activity by different types of cells could provide an explanation for the unique spectrum of tumors associated with NF2 deficiency in mammals [McClatchey & Giovannini 2005].

Abnormal gene product. Abnormal NF2 protein is caused by either a somatic or constitutional mutation.

Attempts to identify truncated protein product have been unsuccessful in the main, although the non-truncated product from missense mutations may have partial function. It is thought that nonsense-mediated decay may account for the lack of identifiable product from most mutational types; however, this does not explain why phenotypes are more severe for this type of mutation than for whole-gene deletions.

Resources

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See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.

References

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Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Suggested Reading

  1. Hanemann CO, Evans DG. News on the genetics, epidemiology, medical care and translational research of Schwannomas. J Neurol. 2006;253:1533–41. [PubMed: 17219030]
  2. Houshmandi SS, Gutmann DH. All in the family: using inherited cancer syndromes to understand de-regulated cell signaling in brain tumors. J Cell Biochem. 2007;102:811–9. [PubMed: 17721931]
  3. MacCollin M, Gusella J. Neurofibromatosis 2. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill; Chap 40. Available at www.ommbid.com. Accessed 8-10-11.

Chapter Notes

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Author History

D Gareth Evans, MD, FRCP (2004-present)
Mia MacCollin, MD; Harvard Medical School (1998-2004)

Revision History

  • 18 August 2011 (DGE) Comprehensive update posted live

  • 19 May 2009 (DGE) Comprehensive update posted live

  • 6 June 2006 (DGE) Comprehensive update posted to live Web site

  • 6 April 2004 (DGE) Comprehensive update posted to live Web site

  • 29 October 2001 (DGE) Comprehensive update posted to live Web site

  • 14 October 1998 (PB) Review posted to live Web site

  • 5 August 1998 (MM) Original submission

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