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Juvenile Polyposis Syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT) via the SMAD4 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
SMAD4 81406 81406,81405 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7519SMAD481406 81406,81405 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Jamie Fox, PhD

Clinical Features and Genetics

Clinical Features

Juvenile polyposis syndrome (JPS; OMIM 608456) is a rare, inherited hamartomatous polyposis syndrome with increased susceptibility to colorectal cancer. Hereditary hemorrhagic telangiectasia (HHT; OMIM 187300) is a disease of vascular dysplasia characterized by the presence of arteriovenous malformations (AVMs). Clinical diagnosis of JPS is typically made when one of the following criteria is met: more than five juvenile polyps in the colorectum; multiple juvenile polyps throughout the GI tract; or any number of juvenile polyps as well as a family history of gastrointestinal polyps (Chow & Macrae J Gastroenterol Hepatol 20:1634-1640, 2005). In JPS, 'juvenile' refers to the developmentally immature nature of the polyp, not the age of disease onset. In addition to polyposis, 10-20% of JPS patients also have extracolonic abnormalities, such as congenital heart defects, cleft lip or palate, microcephaly, and malrotations (Eng et al. Annu Rev Med 52:371-400, 2001). Patients with HHT often have frequent nosebleeds and telangiectases on the lips, hands, and face. About 20-25% of HHT patients develop GI bleeding later in life that may lead to severe anemia (Abdalla et al. J Med Genet 40:494-502, 2003). Cerebral AVMs (5-20% of patients) and pulmonary AVMs (30-50% of patients) are usually present at birth and may cause headaches, seizures, ischemia, hypoxemia, and hemothorax (see Shovlin and Letarte Thorax 54:714-729, 1999). Confirming a diagnosis of JPS or HHT is important for the appropriate surveillance and management of cancer in individuals with juvenile polyps and AVMs in patients with HHT.


Both JPS and HHT can be caused by heterozygous germline variants in the SMAD4 gene (OMIM 600993) (Howe et al. Science 280:1086-1088, 1998; Howe et al. Nat Genet 28:184-187, 2001). Variants in SMAD4 are also found in patients with a combined syndrome of JPS and HHT (JP-HHT). SMAD4 mediates the biological effects of the transforming growth factor-β (TGF-β) superfamily of cytokines (Miyazono et al. J Biochem 147:35-51, 2010). In epithelial cells, the TGF-β pathway normally inhibits growth and proliferation; variants in SMAD4 decrease TGF-β signaling and can lead to AVMs, neoplasia, and carcinoma.

Clinical Sensitivity - Sequencing with CNV PG-Select

This test is predicted to identify a SMAD4 variant in ~20% of patients diagnosed with JPS (Calva-Cerqueira et al. Clin Genet 75:79-85, 2009) or ~ 10% of patients with HHT who do not have variants in other known HHT genes (Gallione et al. J Med Genet 43:793, 2006).

Testing Strategy

This test provides full coverage of all coding exons of the SMAD4 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with a clinical diagnosis of JPS or AVMs. This test is specifically designed to detect germline variants and is not appropriate for the detection of somatic variants in tumors.


Official Gene Symbol OMIM ID
SMAD4 600993
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Comprehensive Cardiology Panel


  • Abdalla, S. A., et.al. (2003). "Visceral manifestations in hereditary haemorrhagic telangiectasia type 2." J Med Genet 40(7): 494-502. PubMed ID: 12843319
  • Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen-Haidle J, Howe J. 2009. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clinical Genetics 75: 79–85. PubMed ID: 18823382
  • Chow E, Macrae F. 2005. A review of Juvenile Polyposis Syndrome. Journal of Gastroenterology and Hepatology 20: 1634–1640. PubMed ID: 16246179
  • Eng C, Hampel H, Chapelle A de la. 2001. Genetic testing for cancer predisposition. Annual review of medicine 52: 371–400. PubMed ID: 11160785
  • Gallione, C. J., et.al. (2006). "SMAD4 mutations found in unselected HHT patients." J Med Genet 43(10): 793-7. PubMed ID: 16613914
  • Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B. 2001. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat. Genet. 28: 184–187. PubMed ID: 11381269
  • Howe JR. 1998. Mutations in the SMAD4/DPC4 Gene in Juvenile Polyposis. Science 280: 1086–1088. PubMed ID: 9582123
  • Miyazono K, Kamiya Y, Morikawa M. 2009. Bone morphogenetic protein receptors and signal transduction. Journal of Biochemistry 147: 35–51. PubMed ID: 19762341
  • Shovlin, C. L., Letarte, M. (1999). "Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms." Thorax 54(8): 714-29. PubMed ID: 10413726


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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