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)


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

Add-on preliminary-evidence gene (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.


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.

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

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. 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 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

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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.