The Invitae Schwannomatosis Panel analyzes the LZTR1, NF2 and SMARCB1 genes, associated with hereditary schwannomatosis.
Testing may be considered in any individual with multiple schwannomas or a family history of schwannomatosis. Individuals with a pathogenic variant are at increased risk of developing multiple schwannomas, primarily along peripheral nerves, that often cause chronic, severe pain that can be debilitating. This test can also distinguish schwannomatosis from neurofibromatosis type 2 (NF2), prior to the development of vestibular schwannomas. Vestibular schwannomas are a hallmark of NF2 and usually develop by 30 years of age; however, vestibular schwannomas are absent in isolated, nonsyndromic schwannomatosis. Individuals with multiple schwannomas may eventually fulfill NF2 diagnostic criteria and some isolated cases are mosaic for a pathogenic variant in NF2. Medical management, natural history, treatment, mortality, and genetic risks differ greatly between schwannomatosis and NF2, so distinguishing the two phenotypes is of critical importance.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
LZTR1 NF2 SMARCB1
LZTR1 NF2 SMARCB1
Schwannomatosis is a rare form of neurofibromatosis that results in multiple schwannomas (a benign myelin sheath tumor derived from Schwann cells). Schwannomas arise primarily along the peripheral nerves but they can also appear along intracranial nerves and/or the spinal nerve root. Schwannomatosis is distinguished from neurofibromatosis type 2 (NF2) in that there are no concomitant bilateral vestibular schwannomas—a diagnostic criterion of NF2.
Affected schwannomatosis patients generally present in the second or third decade of life with chronic, severe pain (although pain intensity varies between individuals) and neurologic dysfunction if the schwannoma is pressing on a nerve or nearby tissue. Overall, symptomatology is widely variable and is dependent upon where schwannomas are located. Additional symptoms can include tingling, weakness due to nerve or spinal cord compression, difficulty with urination or bowel dysfunction, facial weakness, headaches, vision changes, and lumps or swollen areas where tumors form under the skin. Malignant transformation rarely occurs. Some patients may also develop meningiomas (generally benign tumors of meningeal tissue). Up to one third of schwannomatosis patients present with a segmental or mosaic form, in which schwannomas are localized to one limb or five or fewer spinal segmental segments. Life expectancy is normal, but there can be significant morbidity depending upon the location of the schwannomas.
It is difficult to more definitively describe the sensitivity of this test in individuals with schwannomatosis, as a majority of sporadic schwannomatosis cases, as well as individuals with multiple meningiomas, have no known causative mutation.
Single schwannomas occur frequently in the general population and these cases are generally sporadic. The inheritance of schwannomatosis is not well understood and only 15%-25% of such cases are considered hereditary. Hereditary forms due to pathogenic variants in LZTR1, NF2 and SMARCB1 exhibit autosomal dominant inheritance with highly variable expressivity and incomplete penetrance. While most cases of schwannomatosis are inherited from a parent, 10%-30% are the result of a spontaneous de novo mutation (10% for schwannomatosis due to SMARCB1 and 30% for LZTR1). Approximately 25%-30% of simplex NF2 cases are mosaic for an NF2 pathogenic variant.
Schwannomatosis exhibits highly variable expressivity and incomplete penetrance. While penetrance is reduced, the specific lifetime risk of developing schwannomas is currently not established.
The exact incidence of inherited nonsyndromic schwannomatosis is not definitively known, but may be as common as neurofibromatosis type 2, which affects approximately 1 in 40,000 births. There is no known predilection for race or gender.
Testing for schwannomatosis may be indicated in an individual with a family history of multiple schwannomas in a first-degree relative or for diagnostic confirmation in a proband. Current diagnostic criteria for schwannomatosis, published in the American Journal of Medical Genetics Part A, are as follows:
Consider schwannomatosis as a possible diagnosis if there are:
For management guidelines please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|