Test ID: SMADZ    
SMAD4 Gene, Full Gene Analysis, Varies

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.

When this test is ordered, comparative genomic hybridization array will always be performed at an additional charge.

See Colonic Polyposis Syndromes Testing Algorithm in Special Instructions.

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.

An interpretive report will be provided.

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.

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.

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.

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424

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

3. Calva-Cerqueira D, Chinnathambi S, Bechman 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. Larsen Haidle J, Howe JR: Juvenile Polyposis Syndrome. In GeneReviews. University of Washington, Seattle, 1993-2014. 2003 May 13. Edited by RA Pagon, MP Adam, HH Ardinger, et al. Available at www.ncbi.nlm.nih.gov/books/NBK1469

• Molecular Genetics: Inherited Cancer Syndromes Patient Information
• Informed Consent for Genetic Testing
• Colonic Polyposis Syndromes Testing Algorithm
• Informed Consent for Genetic Testing (Spanish)