Gene panel (includes 29 genes)
Basic characteristics of the clinical phenotype:
Approximately 5% of primary brain tumors are characterized by hereditary factors. Hereditary syndromes leading to the development of tumors in the nervous system /CNS and PNS/ are a heterogeneous group of genetic diseases characterized by a combination of systemic manifestations (most often dermatological) and neoplasias in the CNS. The majority of these syndromes are autosomal dominant and include neurofibromatosis type 1 and type 2, tuberous sclerosis, von Hippel-Lindau disease, Turcot syndrome, and Li-Fraumeni syndrome, which have been shown to greatly increase the risk of developing cancer in the nervous system.
Neurofibromatosis type 1 (NF1 or Recklinghausen's disease) is one of the most common genetic syndromes, with an incidence of 1 in 4,000. It is characterized by 100% penetrance and a 50% spontaneous mutation rate. The NF1 gene is located at locus 17q11.2 and encodes the tumor suppressor protein neurofibromin. The predominant amount of CNS tumors with NF1 are those gliomas of the optic nerve and medulla oblongata. Patients with gliomas of the medulla oblongata (MPG) harboring mutations in the NF1 gene are predominantly astrocytomas, although they are considered to be less aggressive and have a significantly better prognosis compared to MPGs that do not possess a mutation in NF1.
Neurofibromatosis type 2 (NF2), also called central neurofibromatosis, with an incidence of 1 in 50,000, accounts for only 10% of all neurofibromatosis cases. The NF2 gene is a tumor suppressor gene located on chromosome 22q12, and encodes the protein merlin (or schwannomin). The majority of CNS tumors harboring NF2 mutations result in cranial nerve VIII (vestibular) schwannomas, which are often bilateral, and cranial meningiomas. Peripheral tumors with mutations in NF2 are spinal schwannomas neurofibromas.
Von Hippel-Lindau disease (VHL) is a disease due to mutations in the tumor-suppressor gene (VHL), with a strong variability in its presentation and an incidence of about 80-90% by age 65. The VHL gene is located on chromosome 3p25-p26. The protein product (pVHL) forms a protein complex (CBCVHL) that often harbors a mutation in VHL, leading to activation of VEGF gene regulation and confirming observations that angiogenesis is an important factor underlying VHL disease pathogenesis. The frequency of the described tumors in the composition of the syndrome varies widely in different families. About 10-20% of all VHL patients develop pheochromocytomas, which have a significantly earlier onset, are more often multifocal, and are less malignant than the sporadic forms.
Tuberous sclerosis affects approximately 1 in 10,000 births, and is the second most common neurocutaneous disease (after NF1). TS is associated with two different loci - TS complex-1 (TSC1), localized on chromosome 9p34 and encoding the protein hamartin, while TS complex-2 (TSC2) is localized on chromosome 16p13.3 and encoding the protein tuberin. Both proteins are thought to have a tumor suppressor function. Approximately 50% of patients with familial TS have a mutation in one of the TSC1 or TSC2 genes.
Li-Fraumeni syndrome (LFS) is a rare inherited disorder affecting children and young adults due to germline mutations in the TP53 gene. The mutations affect the region affecting exons 5 to 9 in p53. Germline mutations in hCHK2, a putative tumor suppressor gene associated with LFS, have been found in patients with familial LFS. The mean age of onset of malignancies in individuals with LFS is between 20 and 45 years of age, which is approximately 2–3 decades earlier than that observed in the general population.
Indications for Referral/ Clinical Significance:
Candidates for this test are all patients with a clinical (medical) or family history suggesting that the etiology of the disease is due to hereditary genetic changes. The test is offered to patients in whom the most common mutations are not detected using Sanger sequencing of the most commonly affected genes.
This test is specifically intended for the analysis of inherited germline mutations and is not suitable for the study of somatic mutations in tumor tissue.
Method: Next-generation sequencing (NovaSeq6000, Illumina).
The method involves bi-directional DNA sequencing of all coding exons and intron-exon boundaries of target genes. The laboratory offers Sanger sequencing of a single exon or a pair of exons in the patient's relatives to determine carrier status in cases where the mutation is known (Test #182).
Sensitivity of the method: depends on GC and AT content, as well as the presence of segmentally duplicated genes.
What does the test involve?
· DNA isolation and sample storage.
· Parallel sequencing including bi-directional DNA sequencing of all coding exons and intron-exon boundaries of target genes
· Bioinformatic analysis of sequencing data. For each patient, only data for the gene(s) of interest were analyzed.
· 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.
