Associated disorders

The SMAD4 gene is associated with autosomal dominant juvenile polyposis syndrome (JPS) (MedGen UID: 87518) and hereditary hemorrhagic telangiectasia (HHT) (MedGen UID: 331400).

The SMAD4 gene encodes a member of the SMAD family of signal transduction proteins. SMAD proteins are activated by transmembrane serine-threonine kinases in response to TGF-beta signaling, and inhibit cell growth and proliferation by mediating transcriptional activation of target genes.

SMAD4—juvenile polyposis
MedGen UID: 87518

Clinical condition
Juvenile polyposis syndrome (JPS) is a cancer predisposition syndrome that is characterized by the development of numerous hamartomatous polyps in the gastrointestinal tract (stomach, small intestine, colon, and rectum). The number of polyps varies from fewer than five to more than 100. Polyposis typically begins in the mid-teens to late twenties, but can also present in childhood. Individuals with JPS develop polyps at a young age and are most often benign, however, the term “juvenile polyp” refers to a specific histologic type of polyp, not the age at diagnosis (PMID: 22965402 25394175 ASCO. Cancer.Net: Juvenile Polyposis Syndrome. Accessed June 2015; National Library of Medicine. Genetics Home Reference: Juvenile Polyposis Syndrome. Accessed June 2015 ). JPS is associated with a 17%-22% risk of colorectal cancer by age 35 and approaches 68% by age 60 (PMID: 20301642 25645574 17303595 16246179 ), a 21% risk of gastric cancer (PMID: 20301642 20859198 9869523 ), and a currently unspecified risk of pancreatic cancer (PMID: 92705469 ASCO. Cancer.Net: Juvenile Polyposis Syndrome. Accessed June 2015 ). There may also be an increased risk for other cancer types, but the current evidence is preliminary. Associated health complications may include rectal bleeding, abdominal pain, anemia, and obstruction.

In some cases, JPS presents in combination with hereditary hemorrhagic telangiectasia (HHT), which is a condition that can also occur as a result of pathogenic variants in the SMAD4 gene. HHT is characterized by epistaxis (nosebleeds) and arteriovenous malformations (AVM) due to abnormal blood vessel development, which may form in the lungs, liver, brain, and gastrointestinal tract (PMID: 20301642 ). The symptoms of HHT may present in early childhood. While the frequency of each HHT complication in individuals with a SMAD4 pathogenic variant is variable and not well-established, recent studies have found that HHT is a significant medical concern. Such individuals would benefit from surveillance for not only juvenile polyps but HHT-related complications as well (PMID: 20301642 ).

Gene information
SMAD4 encodes a member of the Smad family of signal transduction proteins. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and is subject to complex regulation by post-translational modifications. If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers and HHT is increased (NCBI Gene. Gene ID: 4089. Accessed September 24, 2015).

JPS has autosomal dominant inheritance. This means that an individual with a pathogenic variant in SMAD4 has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Most cases are inherited from a parent, but approximately 25% can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it) (PMID: 20301642 ).

To establish the extent of disease in an individual diagnosed with JPS, the following evaluations are recommended (PMID: 20301642 National Comprehensive Cancer Network. Surveillance Guidelines for JPS. Version 1.2015 ):

  • a history for abdominal pain, rectal bleeding, constipation, diarrhea, or change in stool size, shape, or color
  • complete blood count (CBC), colonoscopy, and upper endoscopy at age 15 years or at the time of initial symptoms—whichever is earlier
  • medical genetics consultation
  • due to the increased risk of colorectal cancer, colonoscopies should be performed every 2–3 years—annually, if polyps are found.
    • If only one or a few polyps are identified, the polyps should be removed. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.
    • If many polyps are identified, removal of most of the colon or stomach may be necessary. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.
  • due to a 21% risk of stomach cancer, upper endoscopies should be performed every 2–3 years if there are multiple polyps present—annually, if polyps are found
  • no specific screening/surveillance guidelines have been proposed for small intestinal or pancreatic cancer because they appear to be rare

Early endoscopic polypectomy may reduce morbidity by reducing the risk for cancer, bleeding, or intestinal obstruction. In some cases, removal of all or part of the colon or stomach may be necessary to alleviate symptoms or to reduce cancer risk when a large number of polyps are present (PMID: 20301642 National Comprehensive Cancer Network. Surveillance Guidelines for JPS. Version 1.2015 ).

Due to the additional risk of HHT associated with pathogenic SMAD4 variants, it has been suggested that all affected individuals be evaluated for complications related to HHT (PMID: 20301642 ). The following surveillance guidelines for HHT have been proposed (PMID: 20301525 ):

  • head MRI with and without gadolinium is recommended as early as the first few months of life
    • rescreen for cerebral AVMs through brain MRI after puberty if the initial brain MRI was done in childhood; while most cerebral AVMs are congenital, the development of such lesions within the first two decades of life has been reported and therefore rescreening is recommended
  • annual evaluations for anemia
  • measurement of oxygen saturation via pulse oximetry every one to two years during the first decade of life and every five years by contrast echocardiogram thereafter

Women with HHT considering pregnancy should be screened and treated for pulmonary and cerebral AVMs. Affected pregnant women with undetected and/or untreated AVMs (particularly lung AVMs) are at risk for serious complications; therefore, pulmonary AVMs discovered during pregnancy are treated during the second trimester. Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia (PMID: 20301525 ).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic SMAD4 variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding SMAD4 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow condition-specific screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: December 2015

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
SMAD4 NM_005359.5