Interpretive Handbook

Test 61489 :
SMAD4 Gene, Full Gene Analysis

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.

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

Confirmation of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia for patients with clinical features


This test should be ordered only for individuals with symptoms suggestive of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia. Asymptomatic patients with a family history of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia should not be tested until a mutation 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

A small percentage of individuals who are carriers or have a diagnosis of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia may have a mutation that is not identified by this method (eg, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia. For carrier testing, it is important to first document the presence of a SMAD4 gene mutation in an affected family member.


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


In some cases, DNA alterations of undetermined significance may be identified.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


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


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

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

5. Gallione C, Aylsworth AS, Beis J, et al: Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A 2010;152A(2):333-339

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