Interpretive Handbook

Test 61490 :
SMAD4 Gene, Known Mutation

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Juvenile polyposis syndrome (JPS) is a rare hereditary cancer predisposition syndrome caused by mutations in the SMAD4 or BMPR1A genes. JPS is characterized by the presence of multiple histologically defined juvenile polyps in the upper and/or lower gastrointestinal (GI) tract and an increased risk for GI cancers. Age of onset for cancer development is typically in the second or third decade of life, although some patients present with a more severe infantile-onset form of the disease. JPS is inherited in an autosomal dominant fashion, although a significant proportion of probands have no family history. Approximately 50% of patients with JPS have an identifiable mutation in the SMAD4 or BMPR1A genes.


Of note, some patients with mutations in the SMAD4 gene exhibit a combined juvenile polyposis/hereditary hemorrhagic telangiectasia phenotype (JP/HHT). Clinical features of HHT include development of arteriovenous malformations (AVMs) of the skin, mucosa, and viscera; spontaneous, recurrent epistaxis (nosebleeds); as well as additional complications such as transient ischemic attacks, embolic stroke, heart failure, cerebral abscess, massive hemoptysis, massive hemothorax, seizure, and cerebral hemorrhage.


Note: This test is appropriate for predictive testing in families in which a point mutation or small insertion/deletion/duplication has been identified.


For predictive testing in families in which a large deletion or duplication (whole exon or multi-exon) has been identified, SDEL / Single-Gene Large Deletion and Duplication Analysis is appropriate.


If a familial mutation has not been previously identified, order SMADS / SMAD4 Gene, Full Gene Analysis.

Useful For Suggests clinical disorders or settings where the test may be helpful

Predictive testing for juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia when a point mutation or small insertion/deletion/duplication has been identified in an affected family member

Interpretation Provides information to assist in interpretation of the test results

All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity, and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order SMADS / SMAD4 Gene, Full Gene Analysis.


Analysis is performed for the familial mutation provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with hereditary colorectal cancer.


We strongly recommend that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to erroneous interpretation of results.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 for instructions to testing patients who have received a bone marrow transplant.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008:10(4):294-300

2. Brosens LA, Langeveld D, van Hattern WA, et al: Juvenile polyposis syndrome. World J Gastroenterol 2011;17(44):4839-4844

3. 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

4. Brosens LAA, van Hattern A, Hylind LM, et al: Risk of colorectal cancer in juvenile polyposis. Gut 2007;56:965-967

5. Gallione C, Aylsworth A, Beis J, et al: Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J of Med Genet Part A 2010;152:333-339

6. Juvenile Polyposis Syndrome-GeneReviews-NCBI Bookshelf. Available from URL: