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  • Test code: 01733
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
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Invitae Familial Neuroblastoma Panel

Test description

This test analyzes the ALK and PHOX2B genes, which are associated with familial neuroblastoma. This condition causes an increased risk for the development of malignant or benign tumors that originate from neuroblasts. Such tumors most often develop in the adrenal gland, abdomen, chest, neck, and pelvis.

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.

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Primary panel (2 genes)
Add-on Preliminary-evidence Gene for Familial Neuroblastoma (1 gene)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include a gene which does not currently have a definitive clinical association, but which may prove to be clinically significant in the future. This gene can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

KIF1B

  • familial neuroblastoma

Neuroblastoma is a childhood onset malignancy and develops from neuroblasts. Most commonly, the tumor originates in the adrenal gland with other sites including the abdomen, chest, neck, and pelvis. Neuroblastoma can metastasize to other parts of the body such as the bones, liver, or skin. The spectrum of neuroblastic tumors includes neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is more commonly malignant while ganglioneuroma is a more benign tumor. Depending on tumor-specific histology, ganglioneuroblastomas can behave more aggressively, like neuroblastoma, or in a more benign fashion like a ganglioneuroma.

Those who develop a neuroblastoma may have symptoms including irritability, fever, fatigue, pain, loss of appetite, and weight loss. Further, neuroblastomas can release hormones that may cause other symptoms, such as hypertension, tachypnea, flushed skin, and tachypnea. In rare instances, opsoclonus myoclonus, an autoimmune condition causing rapid eye movements and jerky muscle motions, may develop.

Pathogenic variants in the ALK and PHOX2B genes are associated with a predisposition to developing familial neuroblastoma.

ALK
Pathogenic variants in the ALK gene are the most common genetic cause of familial neuroblastoma.

PHOX2B
PHOX2B pathogenic variants are the second-most common etiology for familial neuroblastoma and are also associated with disorders of neural crest development, including Hirschsprung and congenital central hypoventilation syndrome (CCHS). Individuals with pathogenic PHOX2B variants may also have characteristic dysmorphic features such as downslanting palpebral fissures, small nose, and low-set, posteriorly rotated ears.

**The majority (~92%) of pathogenic variants causing CCHS are caused by a alanine repeat expansion in exon 3 of the PHOX2B gene, which is unavailable on our current assay. Our test of the remainder of the coding sequence is part of our hereditary cancer offerings with the aim of identifying rare individuals with hereditary neuroblastoma.

The risk of neuroblastoma is highest in infancy and decreases by late childhood. Individuals with familial neuroblastoma tend to develop tumors at a younger age (average 9 months) than those without familial predisposition (age 2–3 years). The lifetime risk for malignant neuroblastoma in individuals with a pathogenic variant in ALK and PHOX2B is currently unknown, though preliminary data suggest that it may be as high as 57%.

Familial neuroblastoma is inherited in an autosomal dominant pattern. Some cases are inherited from a parent, and while spontaneous de novo cases have been reported, the incidence of such cases is currently unknown.

Neuroblastoma is the most common cancer in infants younger than 1 year. It occurs in 1 in 100,000 children and is diagnosed in about 650 children each year in the United States. An estimated 1%–2% of individuals with neuroblastoma have a close relative who also has neuroblastoma.

Genetic analysis of the ALK and PHOX2B genes for familial neuroblastoma may be considered in individuals with:

  • a neuroblastic tumor, including neuroblastoma, ganglioneuroblastoma, or ganglioneuroma
  • multiple primary neuroblastic tumors that arise either synchronously or metachronously
  • a family history of one or more relatives with one of the three types of neuroblastic tumors

  1. Mossé, YP, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008; 455(7215):930-5. PMID: 18724359
  2. Bourdeaut, F, et al. ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome. Eur. J. Hum. Genet. 2012; 20(3):291-7. PMID: 22071890
  3. Janoueix-Lerosey, I, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008; 455(7215):967-70. PMID: 18923523
  4. Azarova, AM, et al. Emerging importance of ALK in neuroblastoma. Semin. Cancer Biol. 2011; 21(4):267-75. PMID: 21945349
  5. Yeh, IT, et al. A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors. Hum. Genet. 2008; 124(3):279-85. PMID: 18726616
  6. Irwin, MS, Park, JR. Neuroblastoma: paradigm for precision medicine. Pediatr. Clin. North Am. 2015; 62(1):225-56. PMID: 25435121
  7. Schleiermacher, G, et al. Recent insights into the biology of neuroblastoma. Int. J. Cancer. 2014; 135(10):2249-61. PMID: 25124476
  8. Greengard, EG, Park, JR. ALK-Related Neuroblastic Tumor Susceptibility. 2010 Jan 05. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301782
  9. Park, JR, et al. Neuroblastoma: biology, prognosis, and treatment. Pediatr. Clin. North Am. 2008; 55(1):97-120, x. PMID: 18242317
  10. Rand CM et al., Congenital central hypoventilation syndrome and sudden infant death syndrome: disorders of autonomic regulation. Semin Pediatr Neurol. 2013 Mar;20(1):44-55. doi: 10.1016/j.spen.2013.01.005. PMID: 23465774
  11. Weese-Mayer DE et al., Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation. Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):38-48. doi: 10.1016/j.resp.2008.05.011. PMID: 18579454
  12. Weese-Mayer DE et al., An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med. 2010 Mar 15;181(6):626-44. doi: 10.1164/rccm.200807-1069ST. PMID: 20208042
  13. Genetics Home Reference, Neuroblastoma.

Assay and technical information

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
ALK NM_004304.4
KIF1B NM_015074.3
PHOX2B* NM_003924.3

PHOX2B: Alanine repeat numbers for the commonly expanded region in exon 3 are not determined.