The Invitae Pediatric Nervous System/Brain Tumors Panel analyzes genes associated with an increased risk of developing tumors of the brain and central and peripheral nervous systems in childhood or adolescence. These genes were selected based on the available evidence to date to provide Invitae’s most comprehensive panel for hereditary pediatric brain and nervous system tumors. Many of these genes are also associated with an increased risk of other cancer types.
Recent studies of pediatric cancer patients have reported predisposing pathogenic variants in a number of heritable genes. The results show that approximately 10% of children who develop cancer have an underlying cancer-predisposing condition. Genetic testing of these genes may confirm a diagnosis and can substantially influence the choice of appropriate screening and medical management options for the child and other relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
PTEN: Deletion/duplication analysis covers the promoter region.
AIP ALK APC DICER1 EPCAM HRAS LZTR1 MEN1 MLH1 MSH2 MSH6 NF1 NF2 PHOX2B PMS2 PRKAR1A PTCH1 PTEN RB1 SMARCB1 SMARCE1 SUFU TP53 TSC1 TSC2 VHL
MAX RET SDHA SDHAF2 SDHB SDHC SDHD TMEM127
Head-and-neck paragangliomas are neuroendocrine tumors that may occur in families with hereditary paraganglioma pheochromocytoma (PGL-PCC) syndrome. Clinicians can choose to include eight genes that are associated with PGL-PCC at no additional charge.
AIP ALK APC DICER1 EPCAM HRAS LZTR1 MEN1 MLH1 MSH2 MSH6 NF1 NF2 PHOX2B PMS2 PRKAR1A PTCH1 PTEN RB1 SMARCB1 SMARCE1 SUFU TP53 TSC1 TSC2 VHL
Head-and-neck paragangliomas are neuroendocrine tumors that may occur in families with hereditary paraganglioma pheochromocytoma (PGL-PCC) syndrome. Clinicians can choose to include eight genes that are associated with PGL-PCC at no additional charge.
MAX RET SDHA SDHAF2 SDHB SDHC SDHD TMEM127
Advances in genetic testing and studies of pediatric cancer patients have reported predisposing pathogenic genetic variants in a number of heritable genes. Identification of a hereditary cancer predisposition in childhood or adolescence can substantially influence the choice of appropriate screening and medical management options for the child and other relatives.
Although brain tumors are rare in the general population, they are the most common form of solid tumors among children under the age of 15, representing approximately 20% of all childhood cancers. Central nervous system (CNS) tumors are the most common cancers among children ages 0–19 years. Peripheral nervous system (PNS) tumors are rare in adults and children. Approximately 5%–10% of CNS tumors are hereditary and due to a pathogenic variant; the remainder are isolated and occur sporadically. Unlike sporadic cases, both hereditary CNS and PNS tumors may be syndromic and associated with features outside of the nervous system.
There are more than 120 types of nervous system tumors, including astrocytomas, atypical teratoid rhabdoid tumor (AT/RT), chondrosarcoma, choroid plexus, craniopharyngioma, ependymoma, germ cell tumor, glioblastoma, glioma, medulloblastoma, hemangioblastoma, meningioma, neurofibroma, schwannoma and malignant peripheral nerve sheath tumors, among others.
Individuals with a pathogenic variant in one of these genes have an increased risk to develop pediatric solid tumors of the brain and nervous system compared to the average person, but not everyone with such a variant will actually develop a tumor. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which tumors may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. For gene-associated risks, see the table below.
Gene | Condition | Tumor types | PMIDs/references |
---|---|---|---|
AIP | Familial isolated pituitary adenoma (FIPA) | pituitary adenoma | 23371967, 22720333 |
ALK | Familial neuroblastoma | neuroblastoma | 18724359, 18923523, 22071890, 18923503 |
APC | Familial adenomatous polyposis (FAP) | medulloblastoma | 7661930 |
DICER1 | DICER1 syndrome | pituitary blastoma, pineoblastoma | 25022261, 24839956 |
EPCAM | Constitutional mismatch repair deficiency (CMMR-D) | high-grade glioma, supratentorial primitive neuroectodermal tumors (PNET) | 24737826, 24535705 |
HRAS | Costello syndrome | neuroblastoma | 16443854, 22261753 |
LZTR1 | Schwannomatosis | schwannoma | 25480913, 24362817, 25335493 |
MEN1 | Multiple endocrine neoplasia type 1 (MEN1) | meningioma, spinal ependymoma, schwannomas | 14871962 |
MLH1 | Constitutional mismatch repair deficiency (CMMR-D) | high-grade glioma, supratentorial PNET | 24535705, 24440087, 24737826, 24556086 |
MSH2 | Constitutional mismatch repair deficiency (CMMR-D) | high-grade glioma, supratentorial PNET | 24535705, 24440087, 24737826, 24556086 |
MSH6 | Constitutional mismatch repair deficiency (CMMR-D) | high-grade glioma, supratentorial PNET | 24535705, 24440087, 24737826, 24556086 |
NF1 | Neurofibromatosis type 1 | pheochromocytoma, optic glioma, neurofibromas, other CNS malignancies | 24535705 |
NF2 | Neurofibromatosis type 2 | vestibular schwannoma, spinal schwannoma, meningioma | 24535705, 19652604 |
PHOX2B | Familial neuroblastoma | neuroblastoma, ganglioneuroma, ganglioneuroblastoma | 16888290, 15657873 |
PMS2 | Constitutional mismatch repair deficiency (CMMR-D) | high-grade glioma, supratentorial PNET | 24535705, 24440087, 24737826, 24556086 |
PRKAR1A | Carney complex | psammomatous melanotic schwannoma | 11549623 |
PTCH1 | Basal cell nevus syndrome (Gorlin syndrome) | medulloblastoma | 9231911 |
PTEN | PTEN hamartoma syndrome | Lhermitte-Duclos (dysplastic gangliocytoma of the cerebellum) | 20565722 |
RB1 | Familial retinoblastoma | retinoblastoma | 20301625, 8304343 |
SMARCB1 | Rhabdoid tumor predisposition syndrome, schwannomatosis | rhabdoid tumors, schwannomas | 22434719, 24933152, 21208904, 17357086 |
SMARCE1 | Familial meningioma | clear cell meningioma | 25249420, 25143307 |
SUFU | Basal cell nevus syndrome (Gorlin syndrome) | medulloblastoma | 22508808, 19833601,12068298 |
TP53 | Li-Fraumeni syndrome | astrocytoma, glioblastoma, medulloblastoma, choroid plexus carcinoma | 10864200, 20522432, 24535705 |
TSC1 | Tuberous sclerosis | subependymal giant cell astrocytoma | 9568761 |
TSC2 | Tuberous sclerosis | subependymal giant cell astrocytoma | 9568761 |
VHL | von Hippel Lindau syndrome | hemangioblastoma | 21955200 |
The majority of genes on this panel have an autosomal dominant hereditary predisposition to CNS and PNS tumors. The MLH1, MSH2, MSH6 and PMS2 genes are associated with autosomal recessive constitutional mismatch repair deficiency syndrome (CMMR-D).
Carriers of CMMR-D have an increased risk for adult-onset Lynch syndrome. This information will be included in the test report, when such variants are identified.
The Invitae Pediatric Nervous System/Brain Tumors Panel may be considered for children or young adults with the types of nervous system/brain tumors listed above or whose personal or family history is suggestive of a hereditary nervous system tumor predisposition syndrome, including:
There are also some common, general features suggestive of a hereditary cancer syndrome family. These include:
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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 |
---|---|---|---|
AIP | NM_003977.3 | ||
ALK | NM_004304.4 | ||
APC* | NM_000038.5 | ||
DICER1* | NM_177438.2 | ||
EPCAM* | NM_002354.2 | ||
HRAS | NM_005343.2 | ||
LZTR1 | NM_006767.3 | ||
MAX* | NM_002382.4 | ||
MEN1* | NM_130799.2 | ||
MLH1* | NM_000249.3 | ||
MSH2* | NM_000251.2 | ||
MSH6* | NM_000179.2 | ||
NF1* | NM_000267.3 | ||
NF2 | NM_000268.3 | ||
PHOX2B* | NM_003924.3 | ||
PMS2* | NM_000535.5 | ||
PRKAR1A | NM_002734.4 | ||
PTCH1 | NM_000264.3 | ||
PTEN* | NM_000314.4 | ||
RB1* | NM_000321.2 | ||
RET | NM_020975.4 | ||
SDHA* | NM_004168.3 | ||
SDHAF2 | NM_017841.2 | ||
SDHB | NM_003000.2 | ||
SDHC* | NM_003001.3 | ||
SDHD | NM_003002.3 | ||
SMARCB1 | NM_003073.3 | ||
SMARCE1 | NM_003079.4 | ||
SUFU | NM_016169.3 | ||
TMEM127 | NM_017849.3 | ||
TP53* | NM_000546.5 | ||
TSC1* | NM_000368.4 | ||
TSC2 | NM_000548.3 | ||
VHL | NM_000551.3 |
APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis. Sequencing analysis for exon 5 is limited to cds +/-10 bp.
DICER1: Sequencing analysis for exons 22 includes only cds +/- 10 bp.
EPCAM: Sequencing analysis is not offered for this gene.
MAX: Sequencing analysis for exons 2 includes only cds +/- 10 bp.
MEN1: Sequencing analysis for exon 2 is limited to cds +/-10 bp.
MLH1: Deletion/duplication analysis covers the promoter region. Sequencing analysis for exon 12 is limited to cds +/-10 bp.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation). Sequencing analysis for exons 2, 5 includes only cds +/- 10 bp.
MSH6: Sequencing analysis for exons 7, 10 includes only cds +/- 10 bp.
NF1: Sequencing analysis for exons 2, 7, 25, 41, 48 includes only cds +/- 10 bp.
PHOX2B: Alanine repeat numbers for the commonly-expanded region in exon 3 are not determined.
PMS2: Sequencing analysis for exons 7 includes only cds +/- 10 bp.
PTEN: Deletion/duplication analysis covers the promoter region. Sequencing analysis for exons 8 includes only cds +/- 10 bp.
RB1: Sequencing analysis for exons 15-16 includes only cds +/- 10 bp.
SDHA: Deletion/duplication analysis is not offered for this gene and sequencing analysis is not offered for exon 14. Sequencing analysis for exons 6-8 includes only cds +/- 10 bp.
SDHC: Sequencing analysis for exons 2, 6 includes only cds +/- 10 bp.
TP53: Deletion/duplication analysis covers the promoter region.
TSC1: Sequencing analysis for exons 21 includes only cds +/- 10 bp.