This test analyzes the BMPR1A and SMAD4 genes, which are associated with juvenile polyposis syndrome (JPS). This condition results in the development of gastrointestinal polyps that may become cancerous.
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.
BMPR1A and SMAD4 can also be ordered as part of a broader panel to test for different types of hereditary cancer, including colorectal cancer. Depending on the individual’s family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered for no additional cost.
Juvenile polyposis syndrome (JPS) is a cancer predisposition syndrome characterized by the development of numerous hamartomatous polyps in the gastrointestinal tract. Polyposis typically begins in the mid-teens to late twenties but can also present in childhood. Although individuals with JPS develop polyps at a young age, the term “juvenile” refers to the fact that the majority of polyps remain benign (juvenile) and will not become cancerous. Still, approximately 68% of individuals with JPS will eventually develop cancer, including colorectal and upper gastrointestinal tract cancers.
In some cases, JPS presents in combination with hereditary hemorrhagic telangiectasia (HHT), which is caused by one of the genes associated with JPS (SMAD4). HHT is a condition characterized by arteriovenous malformations (AVMs) due to abnormal blood vessel development; it is characterized by epistaxis (nosebleeds), lung AVMs (in 40% of HHT patients), and, more rarely, brain AVMs.
Although the exact penetrance of JPS is unknown, it appears that the majority of individuals with pathogenic variants in SMAD4 and BMPR1A will develop JPS. JPS is also highly variable, meaning individuals with JPS may present differently, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant.
|Cancer type||Lifetime risk|
Approximately 20%-25% of individuals with JPS have pathogenic variants in BMPR1A and 20% have pathogenic variants in SMAD4.
JPS is inherited in an autosomal dominant pattern. Most cases are inherited, but approximately 25% occur as the result of a spontaneous de novo mutation.
The prevalence of JPS is estimated at 1 in 16,000 to 1 in 100,000.
Testing for JPS should be considered for individuals with at least one of the following:
Criteria for evaluating a family for JPS have been established:
Clinical diagnostic criteria have also been developed:
For management recommendations, 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|
BMPR1A: Deletion/duplication analysis covers the promoter region.