Genetics of Neurofibromatosis Type 1 and Type 2

Updated: Sep 19, 2022
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Neurofibromatosis type 1 (NF1) and type 2 (NF2) are neurocutaneous disorders inherited as autosomal dominant genetic syndromes. Autosomal dominant genetic transmission indicates that one copy of the altered gene is required for phenotypic expression. Autosomal dominant syndromes are characterized by a high rate of mutational change that occurs for the first time in an individual. NF1 and NF2 differ with regard to their age of clinical onset, clinical manifestations, gene loci, and gene protein products; in both conditions, however, the altered gene products have an important role in the dysregulation of tumor suppression. This article focuses on the genetics of NF1 and NF2.

Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1), also known as peripheral neurofibromatosis or von Recklinghausen disease, is an autosomal dominant genetic condition caused by a mutation in or a deletion of the NF1 gene. Only one copy of a mutated or deleted NF1 gene is required to affect an individual. Descendants of an affected individual have a 50% risk of inheriting the altered NF1 gene; however, the phenotype of individuals with NF1 is widely variable, even among genetically related family members. [1]

The NF1 gene product is a cytoplasmic protein called neurofibromin 1, which appears to have diverse functions in many different tissues. Although not all functional aspects of neurofibromin 1 are known, it does activate ras -GTPase. [2] Ras -GTPase is part of a family of related proteins that are universally expressed in cells and are involved in cellular signal transduction. A cascade effect occurs when ras -GTPase is “switched on” by incoming signals, leading to activation of other proteins, which, in turn, activate genes responsible for cell growth and differentiation.

Mutations in ras genes can cause permanent activation of ras proteins. Unintended and overactive signaling inside the cells occurs despite the lack of programmed incoming signals. Consequently, overactive ras -GTPase signaling leads to tumor growth. [3] The neurofibromin 1/ras -GTPase connection has roles in the control of cell proliferation and the suppression of cell overgrowth. [2]

The NF1 phenotype results from loss-of-function mutations of the NF1 gene and, therefore, the absence of neurofibromin 1. This genetic mutation is innate, and clinical symptoms appear early in life and continue over many years. [4, 5, 6]

The NF1 gene is cytogenetically located on the long (q) arm of chromosome 17, at band 11.2 (17q11.2). Over 1000 pathogenic allelic variants of the gene have been identified. Of these variants, many are unique to a family. Mutations that have been observed in the NF1 gene include stop mutations, amino acid substitutions, insertions, deletions (partial or whole), and gross chromosomal rearrangements. Most variants involve sizable truncation of neurofibromin 1, often due to alteration of messenger ribonucleic acid (mRNA) splicing. [1] Patients with NF1 who have a whole NF1 gene deletion (about 4-5% of individuals with NF1) appear to develop a more severe phenotype than do patients with a partial gene deletion.

De novo mutations cause up to 50% of novel NF1 cases. The NF1 gene locus has a higher spontaneous mutation rate than do most gene loci. Usually, gene loci contain tens of thousands of base pairs; the NF1 gene has a very large locus (about 350,000 base pairs, or 350 kilobases), [1, 2] which may account for the observed de novo cases.

The NF1 phenotype is highly penetrant (ie, almost all individuals with an NF1 gene mutation have some phenotypic traits of the syndrome). A wide range of expression also exists among people diagnosed with NF1 (ie, there are varying degrees of clinical severity, with differences noted even within the same family).

Given the highly penetrant nature of NF1, individuals who have an altered NF1 gene will eventually present with some clinical feature of this neurocutaneous syndrome and are at an increased risk of developing benign and/or malignant tumors. Benign tumors seen in persons with NF1 include cutaneous neurofibromas, plexiform neurofibromas, and optic nerve gliomas. Peripheral nerve sheath tumors are frequent malignant neoplasms occurring in patients with NF1, being seen in 10% of cases. [1]

A study by Napolitano et al found in a cohort of patients with NF1 that frameshift and nonsense variants were the mutations that were most commonly associated with spinal deformities (including scoliosis, kyphosis, and joint spondylosis), being present in 23.4% and 21.9% of such cases, respectively. Neurofibromin is potentially truncated or absent due to these mutations. Patients with frameshift mutations were also found to be more likely to suffer from learning disabilities, the odds ratio (OR) being 6.2. [7]

Gene cloning has enabled development of mouse and zebrafish research models with NF1 germline mutations. This genetic engineering feat may ultimately enhance knowledge of the pathogenesis of NF1, as well as generate treatments for the disease. [8, 9]

A "mild neurofibromatosis," ie, an NF1-like syndrome caused by a mutation in the SPRED1 gene, has been reported in a small group of individuals. The SPRED1 gene is cytogenetically located on the long (q) arm of chromosome 15 (15q13.2). Individuals with this syndrome do not have NF1 but instead have a genetically distinct disorder, Legius syndrome. [10] About 5% of patients with an NF1-like phenotype without an identified NF1 gene mutation have Legius syndrome. [11]

The SPRED1 gene codes for the Spred-1 protein. This gene product helps regulate the ras/MAPK signaling pathway, which has roles in cellular proliferation and differentiation, cell movement, and apoptosis (programmed cell death). [12] Since phenotypic overlap with NF1 exists, patients may be initially diagnosed with NF1 based on the cutaneous findings, such as multiple café-au-lait spots and axillary and/or inguinal freckles. [11, 12] However, individuals with Legius syndrome do not develop multiple cutaneous neurofibromas or optic gliomas, since, in contrast with NF1, tumorigenic manifestations are absent in this syndrome. [12]

A study by Santoro et al indicated that the rs35857561 polymorphism in MRVI1 may leave European patients with NF1 susceptible to the development of moyamoya syndrome. In the study, whole exome sequencing was performed on two families, both of European background (Italian and German ancestry), chosen because family members had been diagnosed with moyamoya-complicated NF1. The objective was to identify possible genetic modifiers independent of the NF1 locus that may be associated with the pathogenesis of moyamoya syndrome. The authors determined that the p.P186S substitution (rs35857561) in MRVI1 segregated with moyamoya syndrome in both families and may be a genetic susceptibility factor for the syndrome. [13]

Neurofibromatosis type 2

Neurofibromatosis type 2 (NF2), also called bilateral acoustic neurofibromatosis or central neurofibromatosis, is an autosomal dominant genetic syndrome caused by a mutation in, or a deletion of, the NF2 gene. The NF2 gene codes for the cytoskeletal protein neurofibromin 2 and is cytogenetically located on the long (q) arm of chromosome 22, at band 12.2 (22q12.2). Only one copy of a mutated NF2 gene is required to affect an individual. As with NF1, descendents of an individual with NF2 have a 50% risk of inheriting the altered gene. A de novo mutation occurs in about 50% of individuals with NF2; somatic mosaicism is seen in 25-30% of these de novo cases. [14]

NF2 is characterized by vestibular schwannomas (also called acoustic neuromas), which are benign, slow-growing tumors of the eighth cranial nerve. Meningiomas, ependymomas, and schwannomas of other cranial and peripheral nerves also occur. Malignant astrocytomas are very rare but have been reported. NF2 is considered an adult-onset disease, as the age at onset of symptoms is between 18 and 24 years. Presenting signs in young individuals with NF2 may include posterior subcapsular lens opacities and/or cataracts. By age 30 years, however, almost all individuals with NF2 develop bilateral vestibular schwannomas. [14, 15, 16]

Complete penetrance and variable expression characterize NF2. Tumor size, location, and number differ among affected individuals. Although these tumors are benign, their anatomic location and multiplicity cause significant morbidity and early mortality; the average life expectancy among persons with NF2 is 36 years. [14, 17]

Neurofibromin 2 is also called merlin (moesin-ezrin-radixin – like protein), to denote its similarity to cytoskeletally associated proteins. The name schwannomin has also been proposed, to recognize the role of neurofibromin 2 in preventing schwannoma formation. [14] Merlin is essential to the regulation of contact-dependent inhibition of cellular proliferation. It functions at the cell-cell adhesion interface, in transmembrane signaling, and in the actin cytoskeleton. Merlin is also a tumor suppressor protein. [18] It is predominantly expressed in neurons, Schwann cells, oligodendrocytes, and leukocytes. [16]

About 90% of NF2 gene mutations result in a compromised protein product. In this situation, nonfunctional merlin cannot prevent tumor growth, enabling cells, especially Schwann cells, to rapidly and uncontrollably multiply. Hence, it is understandable that vestibular schwannomas are the most common benign tumors diagnosed in persons with NF2. [14]

A study by Pemov et al indicated that in NF2, initiation of spinal and cranial meningiomas is driven principally, or perhaps solely, by somatic inactivation of the NF2 gene, and that accumulation of copy-number variants, rather than of point mutations, probably results in progression of these tumors. [19]

NF2 is a clinical diagnosis. In affected patients who have a positive family history, the mutation in the NF2 gene can be found through sequence analysis or mutation scanning and through duplication/deletion testing. Prenatal testing can be performed in pregnancies in which the offspring is at increased risk for NF2, if the family specific mutation causing the disease is known or if linkage analysis has been carried out in genetically related family members. [14]


NF Genes

NF1 gene

The NF1 gene is cytogenetically located on the long (q) arm of chromosome 17, band q11.2 (17q11.2), which can be easily recalled based on the fact that the word neurofibromatosis has 17 letters. [20] The NF1 gene has 61 exons [1, 2, 21] and encodes for a cytoplasmic protein called neurofibromin 1.

Neurofibromin 1, an ras -GTPase–activating protein, suppresses tumor growth, primarily by inhibiting ras activity. This protein has a guanosine triphosphatase (GTPase) region that binds to ras proteins and positively modulates conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Its role in tumor suppression has been confirmed in several studies, as truncations in neurofibromin 1 correlate to phenotypic findings seen in individuals with NF1. [21] Loss of neurofibromin 1 function has also been implicated in the molecular pathogenesis of NF1-associated tumors.

A study by Hernández-Imaz et al suggested that mutations in exon 9 on the NF1 gene are so frequent (25% of all exonic alterations associated with splicing in the gene) because of the complexity of the elements on the exon that regulate splicing. The investigators found, for example, that the c.1007G>A mutation produces an exonic splicing silencer element that binds the negative splicing factor hnRNPA1. [22]

NF2 gene

The gene for NF2 is cytogenetically located on the long (q) arm of chromosome 22, band q12.2 (22q12.2) [23] The NF2 gene codes for the protein neurofibromin 2, also called merlin or schwannomin. The NF2 gene spans 110,000 base pairs, or 110 kilobases, and is composed of 16 constitutive exons and one alternatively spliced exon. Individuals with NF2 have wide phenotypic expression. About 200 pathogenic allelic variants have been identified in patients with NF2; most of the altered gene products in this disease result from point mutations. [14, 24, 25]


Genetic Testing

NF1 and NF2 are diagnosed clinically based on established diagnostic criteria. However, to identify mutational changes in the NF1 and NF2 genes, cytogenetic and genetic molecular testing is available. A valuable resource that lists testing options and sample requirements is the Genetic Testing Registry (GTR) of the US National Center for Biotechnology Information (NCBI). [26] Medical geneticists and genetic counselors have the knowledge to assist patients and family members in determining the appropriate diagnostic tests for NF1 and NF2. Additionally, there are many disease-specific and umbrella support organizations in the United States and worldwide to guide and help individuals with these disorders, as well as their families.

Cytogenetically, fluorescent in-situ hybridization (FISH) is used to test for these diseases, including interphase FISH (for NF1 and NF2) and metaphase FISH (for NF1).

However, genetic molecular testing is preferred to diagnose gene mutations in NF1 and NF2. Sera and tissue analysis are used, although in prenatal diagnosis, chorionic villus tissue or amniotic fluid cells are tested. The following are general categories of current genetic molecular testing available for NF1 and NF2 [27] :

  • Comprehensive gene analysis

  • Targeted mutation detection

  • Prenatal detection of a known mutation

  • Comprehensive analysis in affected tissues

Neurofibromatosis type 1

Sequence analysis of the NF1 gene is the preferred molecular diagnostic study for individuals suspected of having NF1. Detection rates using current sequencing methodologies is high (>95%) in clinically affected individuals. [28] Specific genetic molecular testing is useful to confirm the diagnosis in patients with a single phenotypic finding characteristic of NF1 (eg, multiple café-au-lait spots) in the absence of family history.

Patient indicators cited for initiation of genetic molecular testing for an NF1 gene mutation are as follows [27] :

  • Patients who are suspected of having NF1 but who have only one of the diagnostic criteria designated by the National Institutes of Health (NIH)

  • Patients with an atypical presentation of the syndrome

  • Patients who wish to confirm a clinical diagnosis

  • Patients who wish to prepare for prenatal and/or preimplantation diagnosis

For a couple with an affected family member, sequencing can often identify a specific gene mutation. Once the mutation is identified in the proband, prenatal diagnosis using amniotic fluid cells or chorionic villus tissue may be feasible. Preimplantation genetic diagnosis may also be possible, if the couple is willing to undergo in vitro fertilization followed by the transfer of unaffected embryos.

In families with many affected members and no recognizable mutation, linkage analysis is used to track the NF1 gene mutation through multiple generations, to determine the cytogenetic region affected. Prenatal testing for NF1 is possible for these families when the specific mutation has been identified. [1]

Current genetic molecular tests available for NF1 are as follows: [26]

  • Linkage analysis

  • Mutation scanning of the entire coding region

  • Deletion/duplication analysis

  • Sequence analysis of select exons

  • Sequence analysis of the entire coding region

  • Targeted variant analysis

Neurofibromatosis type 2

As with NF1, diagnosis of NF2 is based on clinical criteria. Genetic molecular testing of NF2 includes a combination of sequence analysis or mutation scanning and duplication/deletion testing. This testing approach detects a mutation in most individuals who have a positive family history and are not the first known family member to have NF2. [14]

Indicators cited for the initiation of genetic molecular testing for an NF2 gene mutation are as follows [29] :

  • Proband confirmatory diagnostic testing in a patient in whom no prior mutation was identified

  • Sporadic cases with multiple schwannomas

  • Testing in an affected patient to prepare for predictive testing and anticipatory medical management (ie, the early detection and management of at-risk relatives)

  • Patients who wish to prepare for prenatal and/or preimplantation diagnosis

Current genetic molecular tests available for NF2 are as follows: [26]

  • Linkage analysis

  • Mutation scanning of the entire coding region

  • Deletion/duplication analysis

  • Sequence analysis of select exons

  • Sequence analysis of the entire coding region