Juvenile Polyposis AMPLIFIED™

Juvenile Polyposis Syndrome (JPS) is an autosomal dominant disorder that predisposes to development of hamartomatous polyps in the gastrointestinal tract. Common symptoms include gastrointestinal bleeding, anemia, diarrhea, and abdominal pain. Early detection of JPS allows for better treatment of polyps and surveillance of at-risk individuals. 

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Juvenile Polyposis Syndrome (JPS) is an autosomal dominant disorder that predisposes to development of hamartomatous polyps in the gastrointestinal tract. Common symptoms include gastrointestinal bleeding, anemia, diarrhea, and abdominal pain. Early detection of JPS allows for better treatment of polyps and surveillance of at-risk individuals. 

Malignant transformation can occur, with risk of gastrointestinal cancer ranging from 9% to 50%.

Defects in the BMPR1A and SMAD4 genes cause approximately equal numbers of JPS cases, together accounting for 45-60% of Juvenile Polyposis Syndrome. Sequence variant mutations explain about 40-45% of cases, and the remaining 10-15% of detectable cases are caused by gross deletions of either gene. The Ambry Test: Juvenile Polyposis AMPLIFIED includes concurrent sequence analysis of the BMPR1A and SMAD4 genes with reflex testing to gross Deletion/Duplication Analysis of both genes if no causative mutation is found by Gene Sequence Analysis.

Mutations in the PTEN gene have been reported in a small number of JPS patients, so PTEN sequencing may be considered in BMPR1A- and SMAD4-negative patients. PTEN Testing is available separately.

Disease Name 
Juvenile Polyposis Syndrome (JPS)
HHT, SMAD4-Related
Disease Information 

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder occurring in 1/100,000-1/160,0001 individuals that predisposes to development of polyps in the gastrointestinal tract. Clinical diagnostic criteria for typical JPS require at least three to five colorectal juvenile polyps, juvenile polyps throughout the gastrointestinal tract, or any number of juvenile polyps and a positive family history.2

The term ‘juvenile’ refers to the particular morphology of the polyps, which are hamartomas. Malignant transformation can occur with risk of gastrointestinal cancer ranging from 9% to 50%.3 Polyps are almost always found in the colon and rectum but also occur in the stomach and small intestine. Juvenile polyposis of infancy involves the entire digestive tract and has the poorest prognosis.1 Most other patients develop symptoms by age 20 though some are not diagnosed until the third decade of life. Common symptoms include gastrointestinal bleeding, anemia, diarrhea, and abdominal pain. Early detection of JPS allows for better treatment of polyps and surveillance of at-risk individuals.

Defects in the BMPR1A and SMAD4 genes cause approximately equal numbers of JPS cases, together accounting for 45-60% of JPS. Sequence variant mutations explain about 40-45% of cases, and the remaining 10-15% of detectable cases are caused by gross deletions of either gene.2,4,5

SMAD4 mutations may cause a combined syndrome of Hereditary Hemorrhagic Telangiectasia (HHT) with JPS as reported in 22% of JPS patients with SMAD4 mutations.6 Therefore, clinical evaluation for HHT symptoms is recommended for these patients.4,6 PTEN gene mutations have been reported in a small number of JPS patients, so PTEN sequencing may be considered in BMPR1A- and SMAD4-negative patients.4 PTEN testing is available separately from Ambry Genetics.

Testing Benefits & Indication 

Genetic testing can complement pathology findings to enable:

  • confirmation of diagnosis in symptomatic individuals
  • appropriately increased or decreased surveillance in potentially at-risk relatives who are tested
Test Description 

Juvenile Polyposis AMPLIFIED™ includes concurrent sequence analyses of the BMPR1A and SMAD4 genes with reflex testing to gross deletion/duplication analyses of both genes if no causative mutation is found by sequence analysis. PCR-based double-stranded automated sequencing is performed in the sense and antisense directions for coding exons 3-13 of BMPR1A and exons 1-11 of SMAD4, plus at least 20 bases into the 5’ and 3’ ends of all the introns. If no mutation is detected, analysis of both genes for gross deletions/duplications of any exon is performed by MLPA.

Other test options available are sequence analysis for only one of the genes, deletion/duplication analysis for the pair of genes without sequence analysis, or specific mutation analysis for individual BMPR1A or SMAD4 mutations known to be in the family.

Mutation Detection Rate 

The Juvenile Polyposis AMPLIFIED™ test is designed and validated to detect approximately 99% of described mutations in BMPR1A and SMAD4 (analytic sensitivity). These detectable mutations account for approximately 45-60% of JPS cases (clinical sensitivity).

Specimen Requirements 

Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice.  
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

Turnaround Time 
Technique Days
SMAD4 Gene Sequence Analysis 10-21
BMPR1A Gene Sequence Analysis 10-21
BMPR1A and SMAD4 Deletion / Duplication Analysis 7-14
JPS Gene Sequence Analysis BMPR1A, SMAD4 Reflex Option to Deletion / Duplication 14-35
JPS Gene Sequence Analysis BMPR1A, SMAD4 Concurrent to Deletion / Duplication 14-28
If sequencing is informative and deletion / duplication is cancelled  
JPS Any Single Gene Deletion / Duplication 7-14

 

Specialty 
Genes 
References 

1. Chow E and Macrae F. A review of juvenile polyposis syndrome. J Gastroenterol Hepatol. 2005;20:1634-1640. [PMID: 16246179]

2. Van Hattem WA, Brosens LAA, de Leng WW, et al. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut. 2008;57:623-627. [PMID: 18178612]

3. Merg A and Howe JR. Genetic conditions associated with intestinal juvenile polyps. Am J Med Genet Part C Semin Med Genet. 2004;129C:44-55. [PMID: 15264272]

4. Aretz S, Stienen D, Uhlhaas S, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007;44:702-709. [PMID: 17873119]

5. Calva-Cerqueira D, Chinnathambi S, Pechman B, et al. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 2009:75;79-85. [PMID: 18823382]

6. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363:852-859. [PMID: 15031030]