Associated disorders

The ALK gene is associated with autosomal dominant neuroblastoma susceptibility (MedGen UID: 414083).

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The ALK gene encodes anaplastic lymphoma kinase, one of a family of receptor tyrosine kinases involved in cell signaling that is important for cell growth, proliferation and differentiation. The ALK gene is expressed in the developing nervous system and is thought to be involved in the regulation of neuronal differentiation.

ALK Heterozygote
MedGen UID: 414083

Clinical condition
The ALK gene is associated with autosomal dominant neuroblastoma susceptibility. Neuroblastoma is a tumor that forms among developing nerve cells, and therefore most often affects infants and young children (PMID: 18242317). Studies have identified variants in the ALK gene in families exhibiting a predisposition neuroblastoma (PMID: 18724359, 18923523, 18923524, 22071890). Individuals with a pathogenic variant in ALK are at increased risk of developing a spectrum of neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is often malignant while ganglioneuroma is typically benign; ganglioneuroblastoma can behave similarly to a neuroblastoma or a ganglioneuroma (PMID: 20301782).

Individuals with pathogenic variants in ALK also have an increased risk of developing of multiple primary tumors. The multiple primary tumors may be bilateral adrenal or multiple primary extra-adrenal tumors that can occur either synchronously or metachronously (PMID: 18724359, 18242317, 22071890).

The risk of developing a neuroblastoma is highest in infancy and decreases by late childhood. Individuals with a pathogenic variant in ALK tend to develop tumors at a younger age (average 9 months) compared with sporadic tumors (age 2-3 years) (PMID: 18242317). Due to the rarity of these cases, precise lifetime risks are not well-established. It has been suggested that the overall penetrance for this cancer predisposition syndrome is approximately 57% (PMID: 18923503, 18724359, 18923523, 18923524).

Gene information
The ALK gene encodes a tyrosine kinase receptor which belongs to the insulin receptor superfamily. This protein plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system (NCBI. Gene. Gene ID: 238. Accessed March 2016). If there is a pathogenic variant in this gene that prevents it from normally functioning, there may be an increased risk to develop certain types of cancers.

Hereditary predisposition to cancer due to pathogenic variants in the ALK gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it).

There is currently no clear consensus regarding a screening and surveillance protocol for individuals with pathogenic ALK variants. In the absence of published guidelines, noninvasive measures including physical examination, abdominal ultrasound, and measurement of urine catecholamine metabolite levels have been suggested, although less frequent intervals may also be appropriate (PMID: 20301782, 26539795).

  • Physical examination to assess for clinical manifestations of neuroblastic tumors
    • Every 1-2 months in infants age ≤12 months
    • Every 3-4 months in children age ≤10 years
  • At the time of diagnosis, abdominal ultrasound and chest and abdominal X-rays to assess the most common sites for neuroblastic tumor development
  • Abdominal ultrasound
    • Every 1-2 months in infants age ≤12 months
    • Every 3-4 months in children age ≤10 years
  • Measurement of urine catecholamines, as homovanillic acid and vanillylmendelic acid may be elevated in the presence of a neuroblastic tumor
    • Every 1-2 months in infants age ≤12 months
    • Every 3-4 months in children age ≤10 years
  • Medical genetics consultation

For children who develop neuroblastic tumors, evaluation and treatment should be performed by a pediatric oncologist at a pediatric cancer center (PMID: 20301782). The treatment is the same standard risk-stratified therapy used to treat all neuroblastic tumors (PMID: 20301782). The management guidelines for treating neuroblastoma and ganglioneuroblastoma are complex and depend upon the age of the affected individual, tumor stage and biologic characteristics (PMID: 25435121).

After successful treatment of a neuroblastic tumor, surveillance should continue in children with pathogenic variants in ALK due to the risk of developing multiple primary tumors. There is no consensus on the duration of this screening, however (PMID: 22071890).

Ultimately, an individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Review date: March 2016

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