Characteristics of the test: (includes 1 gene)
NF2 (OMIM #607379)
Basic characteristics of the clinical phenotype:
Neurofibromatosis is a genetic disease that leads to the development of tumors affecting the entire nervous system (brain and spinal cord, nerves), characteristic "coffee with milk" skin pigmentation, forming a multiple, mostly benign fibromatous skin tumors - the so-called neurofibromas.
It is most often diagnosed in childhood or early adulthood. Symptoms are often mild, but complications of the disease can lead to hearing loss, mental retardation, problems with the cardiovascular system, loss of vision, and severe pain.
Neurofibromatosis (benign) or the so-called von Recklinghausen's disease comes in two separate, genetically and clinically distinct forms – type 1 and type 2.
Neurofibromatosis type 2 (NF2), also called central neurofibromatosis, is an autosomal dominant multiple neoplastic syndrome characterized by the forming a tumors in the central and peripheral nervous system. The eighth cranial nerve is most often affected (usually bilaterally), forming schwannomas in the CNS, and when affecting the dorsal endings of the spinal cord, schwannomas, meningiomas and neurofibromas form in the peripheral nervous system.
The incidence of the disease is 1 in 25,000-40,000 live births, and the estimated prevalence in the general population is 1 in 60,000, affecting both sexes, different races and ethnic groups equally. It is considered a late form of neurofibromatosis with an average age of onset of the disease around the age of twenty. About half of the affected individuals present the first cases in the family as a consequence of new (de novo) spontaneous mutations. NF2 occurs in 100% of cases. Children of a parent with NF2 are assumed to have a 50% risk of developing the disease. Individuals with somatic mosaicism and bilateral VS (vestibular schwannoma) have less than a 50% risk of having an affected child.
Although most tumors in NF2 are nonmalignant and grow slowly, their anatomical location and multiplicity lead to progressive compression of adjacent neural and vascular structures, high morbidity and mortality at a young age.
The most common tumors of central neurofibromatosis are schwannomas (uni- or bilateral vestibular schwannomas) and meningiomas.
Bilateral schwannomas (VS) of the vestibular nerves are considered the hallmark of NF2, followed by focal weakness, tinnitus, hearing loss, balance problems, sensory loss, vision loss, but carriers of mutations in the gene may remain and asymptomatic (Bookshelf ID: NBK1201PMID: 20301380). Subsequently, patients develop schwannomas of other cranial and peripheral nerves, as well as of the dorsal roots of the spinal cord. In this condition, meningiomas of the brain and spine occur in 50-60% of cases.
Approximately 40% of patients have multiple meningiomas. In affected individuals, in addition to schwannomas and meningiomas, there are also low-grade CNS tumors of neuro-ectodermal origin (ependymomas, gliomas).
NF2 is caused by mutations inactivating the tumor suppressor gene NF2, located in the long arm of chromosome 22 (22q12.2) and determining the synthesis of the protein schwannomin (merlin), localized in vestibular cells and acting as a membrane-stabilizing protein. Inactivation of the gene occurs by the mechanism of a double hit - through a germline mutation and a subsequent somatic mutation.
Mutations in the gene can be large deletions or rearrangements, nonsense, missense mutations, mutations leading to a shift in the reading frame or affecting splicing. Mutational analysis of NF2 in patients with typical NF2 clinical presentation detects the disease-causing mutation in ~85% of cases. The remaining approximately 10-15% of NF2 patients are characterized by large deletions or duplications. Phenotype-genotype correlations show a difference in disease severity according to the type of mutation – missense and splicing mutations are characterized by a milder clinical manifestation compared to frameshift and nonsense mutations.
Mutations in exons 1 to 5 are characterized by a more severe phenotype compared to those in exons 11–15 (Baser et al. 2004; Baser et al. 2005). Mutations in the 3' end and especially in exons 14-16 are associated with a lower risk of developing meningiomas and milder clinical presentation (Smith et al 2011).
Approximately 50% of patients with an NF2 mutation inherit a germline mutation from an affected parent, and the remaining half are sporadic cases due to de novo mutations. (Abo-Dalo et al. 2010; Halliday et al. 2017; Kluwe et al. 2005; Smith et al. 2016).
Over 30% of cases of new-onset disease result from mosaicism involving NF2 mutations, which may lead to subclinical symptoms and/or difficulty with mutation detection, leading to a false-negative diagnosis (Evans et al. 2007). Pathogenic mutations known so far are characterized by penetrance close to 100%.
Indications for Referral / Clinical Significance:
For the study of large deletions/duplications, rearrangements in the NF2 gene, patients diagnosed with Neurofibromatosis type 2 and without detected mutations in the NF2 gene or close relatives of patients in whom an aberration in the NF2 gene was detected are referred.
Interpretation of results:
Detection of deletions/duplications/rearrangements in the NF2 gene allows the diagnosis of Neurofibromatosis type 2
· The genetic counselor will interpret and answer all questions about your result.
Method: MLPA (Multiplex Ligation Dependent Probe Amplification)
MLPA is a semi-quantitative method for determining copy number variations of DNA. The methodology is used to detect intragenic or whole-gene deletions or duplications. The analysis for searching Large deletion/duplication is performed using the kit SALSA MLPA P044 NF2, developed by MRC-Holland (Amsterdam, Holland).
Sensitivity of the method: 90%
What does the test involve?
· DNA isolation and sample storage.
· MLPA to detect large deletions/duplications affecting the NF2 gene.
· Forming a written result of the genetic test.
· Diagnostic interpretation of results and genetic counseling.
Biological material: Venous blood or DNA
For more information, please read the "Biological material requirements and shipping information" carefully.
