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. 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 

TESTING BENEFITS & INDICATIONS
Genetic testing can complement pathology findings to enable:
       • confirmation of diagnosis in symptomatic individuals
       • appropriately increased or decreased surveillance in 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: Send 20 µg in TE at 50-100 ng/µl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

REFERENCES
¹ Chow E and Macrae F. J Gastroenterol Hepatol. 2005;20:1634-1640.
² Van Hattem WA, Brosens LAA, de Leng WW, et al. Gut. 2008;57:623-627.
³ Merg A and Howe JR. Am J Med Genet Part C (Semin Med Genet). 2004;129C:44-55.
⁴ Aretz S, Stienen D, Uhlhaas S, et al. J Med Genet. 2007;44:702-709.
⁵ Calva-Cerqueira D, Chinnathambi S, Pechman B, et al. Clin Genet. 2009:75;79-85.
⁶ Gallione CJ, Repetto GM, Legius E, et al. Lancet. 2004;363:852-859.

DISCLAIMER
These tests were developed and their performance characteristics were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing.  The gene sequence analysis component of the tests analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions, and small indels.  It is not intended to analyze the following types of mutations: gross deletions and insertions, gross rearrangements, deep intronic variations, and other unknown abnormalities. The complete Juvenile Polyposis AMPLIFIED test analyzes, in addition, gross deletions and duplications. The pattern of mutation types varies with the gene tested and the Juvenile Polyposis AMPLIFIED test detects a high but variable percentage of known and unknown mutants of the classes stated.  A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. Juvenile polyposis syndrome is a complex clinical disorder, which in some cases is due to alterations in BMPR1A or SMAD4 genes generally detected by Juvenile Polyposis AMPLIFIED except as noted above. Mutations in other genes or the regions not tested by the Ambry tests can also give rise to clinical conditions similar to juvenile polyposis syndrome.  Although molecular tests are highly accurate, rare diagnostic errors may occur.  Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, clerical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature.