Genetics

1. Highlights

1. Neurofibromatosis type 2 (NF2), is a rare genetic condition, that does not skip generations.
2. NF2 is a genetic, autosomal dominant condition.
3. All individuals born with NF2 will develop tumors.
4. NF2 is often the result in of spontaneous mutation, spontaneous NF2, or mosaic NF2.
5. With NF2, four-hundred (400) different genetic mutations of chromosome 22 that can cause NF2; these are different breaks in the DNA.
6. NF2 can result in the growth of tumors; 1) schwannoma, 2) meningioma, and 3) ependymoma.
7. 95-98% of people with NF2 develop tumors that result in complete hearing loss. Bilateral, left and right ear from vestibular schwannoma (VS) tumors.
8. It is possible for a person to develop a VS tumor without having NF2, but NF2 is the only reason for bilateral VS. VS growth without NF2 is called spontaneous VS.
9. Schwannoma tumors can grow as a result of the condition schwannomatosis (SWN).
10. NF2 tumors typically remain benign and rarely become malignant.

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2. Introduction

Neurofibromatosis type 2 (NF2) is a rare tumor predisposition, neurological, and genetic, autosomal dominant condition. NF2 is a condition that starts during cellular development before birth. Tumor symptoms of NF2 develop typically in teen years, with possible eye issues can develop early childhood.

Autosomal dominant genetic conditions that of the two genes, alleles, passed from parents during fertilization, only one parent, either male or femele, needs to carry the mutation for the condition to pass the condition to the child.

The mutation can pass during reproduction at fertilization of either; 1) germ line the ovum by the sperm, one parent has the condition, or 2) later in embryonic development. If NF2 started a few cell division growth during fetal instead of at fertilization development, will determine how many cells of the body will have damaged NF cells. The point of NF2 development determines how much of the body is at risk of NF; left side, right side, arms, legs, chest, spine or brain. Later cellular development of NF2 could be in the part of the body the mutation would not have had issues, and this is often why their children may have NF in every cell, while the parent has no NF issues.

3. The 3 Forms of NF

There are three forms of NF; NF1, NF2, and NF3 also known as Schwannomatosis or SWN.

• NF1: is associated with a mutation in the NF1 gene on chromosome 17 which results in improper function of the Ras-GTPase pathway. Chromosome 17q11.2
• NF2: is caused by a mutation in the NF2 gene. There are 693 genes on chromosome 22. The condition of NF2 results in improper function of the Epidermal Growth Factor Receptor (EGFR) Pathway. Chromosome 22q12.2
• Schwannomatosis: is caused by a mutation in the SMARCB1 gene (SWI/SNF) or the LZTR1 gene.
• NF2 and Schwannomatosis: are both located in genes on chromosome 22 and are a lot closer in the traits expressed, but are associated with different genes along chromosome 22.
• NF1 and Schwannomatosis: are similar in the high percentage of tumors along nerves in the body than NF2 but NF1 are Neurofibroma tumors, and Schwannomatosis tumors are Schwannoma tumors.

If a parent has neurofibromatosis type 1 (NF1), their child is at risk of also having NF1. If a parent has neurofibromatosis type 2 (NF2), their child is at risk of also having NF2. If a parent has schwannomatosis/neurofibromatosis type 3 (SWN/NF3), their child might also have NF3. With neurofibromatosis (NF) a parent has, will be the type a child will have, even if what issues of NF a parent has might be different in some way for the child. Like NF2, and NF1, and SWN are autosomal Dominant conditions.^{[Evans, June 2017]}

All forms of NF are neurological conditions where tumors develop and grow at a particular rate. However, the three forms of NF are otherwise completely different disorders. Tumor types common to specific regions of the body and are typically different for all three forms of NF.

4. Development of Neurofibromatosis Type 2

Genes can be found on different chromosomes in the body are specifically for tumor growth blockers, in the case of people with NF2, if the missing NF2 gene results in the development of the protein called MERLIN. Unfortunately, MERLIN also results in more than tumor growth. When the body develops MERLIN, it is unable to prevent tumor growth which results in different combinations of tumors and locations in different parts of the body. While exposure to items that can cause increased growth of tumors of certain types, and in certain locations in the body, tumors will grow regardless of environmental variables like food or toxins.

Different mutations of NF2, ways the chromosome is broken, determines if a person may only have Bilateral Vestibular Schwannoma, or may also have spinal cord Schwannoma, or brain Meningioma as well. There are dozens of combinations of differences. There are many combinations of possible issues a person may or may not have based on exact mutation. There are over 400 known mutations of the gene.

If an individual has a mutation with the possibility of; Bilateral Vestibular Schwannoma, Spinal-cord Schwannoma, and brain Meningioma, but developed the NF2 condition late in fetal development, they could potentially only grow Bilateral Vestibular Schwannoma. Where children they may eventually have would be at risk of tumor formation in all the three regions their parent did not, at either the same or faster rate of growth and possibly earlier in life.

NF2 is an autosomal dominant condition when inherited from family members, Germ Line. However, NF2 can also occur as a new, Spontaneous Mutation.

2.1. Autosomal Dominant - Inherited Mutation

An autosomal dominant genetic condition can be passed down through families. This method of inheritance does not "skip" generations. If a condition is inherited as the result of Autosomal Dominance, it means an individual only need to get the gene from one parent, if a parent has an autosomal dominant condition.

The inheritance of a condition, disorder or trait depends on two main things, the type of chromosome it's on and the kind of trait it is. The trait could be a gene on one of the first 22 chromosomes called autosomal or on a sex chromosome, X or Y, the 23rd chromosome. The second thing the inheritance depends on is the type of trait, a dominant or recessive one.

2.2 Spontaneous Mutation - New Mutation

It is not uncommon for NF to also be a result of a Spontaneous Mutation, also known as de novo mutation (New Mutation). In a Spontaneous Mutation, there is no family history of NF2. Approximately 50% of NF patients' doctors see, have it as a result of a Spontaneous Mutation.

Frequently in Sporadic Mutations of NF2; Mosaicism occurs. People with a Mosaic mutation of a genetic condition; do not have the mutation in every cell in their body.

2.3. Rate to Pass

The following is the explanation for the Autosomal Dominance chart.

• 50% of the parent's offspring have NF2 as expected. They got the chromosome from their father that has the bad gene on it.
• The other two siblings do not have NF2. They got the chromosome from their father that has the good gene on it.
• All children got a chromosome from their mother that has a good gene on it because she does not have NF2
• The first affected son on the left has a 50% chance of passing NF2 to his children.
• The unaffected children have the 0% chance of passing NF2 on but the offspring have a normal population 1:33,000 chance of getting NF2.
• The last daughter has NF2 and will pass it to 50% of her children.
• Each child that the affected boy and girl produce when they grow up has an independent 50% chance of getting NF2 no matter what their siblings or cousins get.

A few factors are responsible for the rate a parent has of having a child with NF2.

1. Parents without NF2: Risk of unaffected parents having a child with NF2 is estimated at 1 in every 25,000 - 60,000 births.
2. One Parent with NF2: If one parent has NF2, risk rates for children are as follows:
   • a parent with only Unilateral Vestibular Schwannoma is (10% of individuals with NF2 develop VS tumors on only one side); 1 in 12
   • a parent with Bilateral Vestibular Schwannoma and no identifiable NF2 mutation in blood; 1 in 8
   • a Mosaic parent with NF2 transmitting the condition to their offspring when mutation cannot be identified; 34%
   • all other cases of NF2 the rate is: 50%

5. NF2 gene and MERLIN

"The NF2 gene provides instructions for the production of a protein called MERLIN (moesin-ezrin-radixin-like protein), also known as Schwannomin. This protein is made in the nervous system, particularly in specialized cells called Schwann cells that wrap around and insulate nerves.

Merlin helps regulate several key signaling pathways that are important for controlling cell shape, cell growth, and the attachment of cells to one another (cell adhesion). This protein functions as a tumor suppressor, preventing cells from growing and dividing too fast or in an uncontrolled way.

The NF2 gene mutations that cause Neurofibromatosis Type 2 are classified as Germline, which means they are present in all of the body's cells. Most NF2 gene mutations result in an abnormally shortened version of the merlin protein. This short protein cannot perform its normal tumor suppressor function in cells. Research suggests that the loss of Merlin's function allows certain cells in the nervous system, especially Schwann cells, to multiply too frequently and form tumors.

More than four-hundred (400) mutations in the NF2 gene have been identified in people with the condition Neurofibromatosis Type 2 (NF2)." ^{[Genetics Home Reference, NF2 gene - neurofibromin 2]}

Cytogenetic Location: 22q12.2

Loss or inactivation of the NF2 gene is often associated with the development of single (isolated) nervous system tumors, including meningiomas, ependymomas, and schwannomas. ^{[Genetics Home Reference, NF2 gene - neurofibromin 2]}

NF2 mutations and/or Merlin inactivation are also seen in other cancers including some mesothelioma, breast cancer, colorectal carcinoma, melanoma and glioblastoma.

6. Different Gene Mutations

Initially, the NF2 condition was believed to include two forms of NF2; Wishart and Gardner, understanding of genetics proved that NF2 is a lot more complicated than just two forms and is now understood to be up to 400 mutations of NF2 due to how the body reacts to the missing or mutated NF2 gene. Wishart was said to be the milder form than Gardner. Also, the same severity of NF2 within a family assumes for autosomal dominant inheritance and not as a Spontaneous mutation; this means if a child will have similar growth rate and issues as family, assuming the family with NF2 was not Mosaic and had NF2 in every cell in their body.

An individual, who has NF2 through spontaneous mutation, may be mosaic and might not have NF2 in their entire body depending on when in embryonic development the NF2 mutation occurred. These individuals might have more of a mild case then their children.

Some of the other variations and mutations include:

• Nonsense
• Frameshift Deletion
• Frameshift Insertion
• Indel
• Splice Donor Site
• Splice Acceptor Site
• Mosaicism
• Missense
• In-frame Deletion
• In-frame Insertion
• Large Deletion
• Large Insertion
• Chromosomal Translocation

6. Spontaneous Vestibular Schwannoma

Sporadic VS, VS not a result of NF2, are very uncommon in young population, at or before adolescence.

Sporadic VS and NF2 VS are both benign, Spontaneous VS damage hearing in one ear, not both like NF2, but like NF2 also result in tinnitus, possible facial paralysis, and life-threatening neurological symptoms if not surgically managed.[Chen, 2014]

7. Phelan-McDermid Syndrome (PMS) (Ring Chromosome 22)

Individuals who are born with Ring Chromosome 22; may also develop NF2, as a result of damage to the 22nd chromosome.

Ring 22 is not a result of NF2; it is the result of a poor formation of the entire twenty-second Chromosome that has many issues but can result in NF2 as well as all the other issues associated with it.

8. Sources

1. Evans, D. Gareth. "Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders" American Association of Cancer Research. Clinical Cancer Research. (June 2017) Source: http://clincancerres.aacrjournals.org/content/23/12/e54 | DOI: 10.1158/1078-0432.CCR-17-0590
2. Ruttledge, M. H., & Rouleau, G. A. "Role of the neurofibromatosis type 2 gene in the development of tumors of the nervous system." Neurosurgical focus, 19(5), 1-5.(2005) Source: http://thejns.org/doi/abs/10.3171/foc.2005.19.5.7
3. Zirn, B., et al. "Ring chromosome 22 and neurofibromatosis type II: proof of two-hit model for the loss of the NF2 gene in the development of meningioma." Clinical genetics 81.1 : 82-87. (2012) http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0004.2010.01598.x/full | DOI: 10.1111/j.1399-0004.2010.01598.x
4. Chen, H., Zhang, X., Zhang, Z., Yang, T., Wang, Z., & Wu, H. "The role of NF2 gene mutations and pathogenesis-related proteins in sporadic vestibular schwannomas in young individuals." Molecular and cellular biochemistry, 1-8. (2014) Source: http://link.springer.com/article/10.1007/s11010-014-2011-9 | DOI: 10.1007/s11010-014-2011-9
5. Genetics Home Reference. U.S. Department of Health & Human Services. "NF2 gene - neurofibromin 2" (Reviewed: January 2017, Published: July 18, 2017) Source: https://ghr.nlm.nih.gov/gene/NF2#conditions
6. OMIM - Online Mendelian Inheritance in Man. "#101000 NEUROFIBROMATOSIS, TYPE II; NF2" https://www.omim.org/entry/101000
7. OMIM - Online Mendelian Inheritance in Man. "#162091 SCHWANNOMATOSIS 1; SWNTS1" https://www.omim.org/entry/162091
8. Genetic Home Reference "NF1 gene, neurofibromin 1" https://ghr.nlm.nih.gov/gene/NF1
9. OMIM - Online Mendelian Inheritance in Man. " * 613113 - NEUROFIBROMIN 1; NF1" https://www.omim.org/entry/613113