Juvenile Polyposis Syndrome: SMAD4 Gene Sequencing

Condition Description

Juvenilepolyposis syndrome (JPS) is an autosomal dominant condition characterized bypredisposition to hamartomatous polyps in the gastrointestinal (GI) tract,specifically in the stomach, small intestine, colon, and rectum. The term\"juvenile\" refers to the type of polyp rather than to the age ofonset of polyps. Most individuals with JPS have some polyps by age 20 years;some may have only four or five polyps over their lifetime, whereas others inthe same family may have more than a hundred. If the polyps are left untreated,they may cause bleeding and anemia. Most juvenile polyps are benign; however,malignant transformation can occur. Most of this increased risk is attributedto colon cancer, but cancers of the stomach, upper GI tract, and pancreas havebeen reported. The incidence of colorectal cancer is 17%-22% by age 35 yearsand approaches 68% by age 60 years. The median age is 42 years. The incidenceof gastric cancer is 21% in those with gastric polyps.

JPS isclinically diagnosed if any one of the three following findings is present:more than five juvenile polyps of the colorectum; multiple juvenile polypsthroughout the GI tract; any number of juvenile polyps and a family history ofjuvenile polyps. Juvenile polyps are hamartomas with a distinct histology thatdiffers from that of adenomas. The genes known to be associated with JPS are SMAD4 and BMPR1A. Approximately 20%of individuals with JPS have mutations in SMAD4(18q21.1); approximately 20% have mutations in BMPR1A. Recent studiessuggest that deletion/duplication testing can identify an additional 9%-14% ofmutations in SMAD4. Approximately 75% of individuals with JPS have anaffected parent; approximately 25% of probands with JPS have no previoushistory of polyps in the family and may have the disorder as the result of anew gene mutation.

Acombined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT)(termed JPS/HHT) may be present in 15%-22% of individuals with an SMAD4mutation. Some clinicians suggest that patients with juvenile polyposis whohave a SMAD4 mutation should bescreened for the vascular lesions associated with hereditary hemorrhagictelangiectasia, especially occult arteriovenous malformations in visceralorgans that may otherwise present suddenly with serious medical consequences.

For patients with suspected JPS, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

Click here for the GeneTests summary on this condition.

Genes (1)

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This test is indicated for:

  • Confirmation of a clinical diagnosis of juvenile polyposis syndrome
  • Individuals at-risk for juvenile polyposis syndrome due to family history


PCR amplification of 11 exons contained in the SMAD4 gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.


Clinical Sensitivity: Approximately 20% of individuals with JPS have mutations in SMAD4 Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient''''s biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (eglgc@egl-eurofins.com).
Submit only 1 of the following specimen types
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the SMAD4 gene by CGH array is available for those individuals in whom sequence analysis is negative (UU).
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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