Juvenile Polyposis Syndrome, BMPR1A Sequencing and Deletion/Duplication

  • Use to confirm a diagnosis of JPS syndrome in symptomatic individuals.
  • Do not use for presymptomatic or diagnostic testing when a causative BMPR1A variant has previously been identified in the family.
Related Tests
  • May assist in the diagnosis of JPS
  • Recommended test if clinical suspicion is for SMAD4 pathogenic variant
  • Recommended test when there is a known familial pathogenic sequence variant previously identified in a family member
  • A copy of the family member’s lab report documenting the familial variant is REQUIRED.
  • Recommended test when there is a known familial pathogenic deletion/duplication variant previously identified in family member
  • A copy of the family member’s lab report documenting the familial variant is REQUIRED.

Juvenile polyposis syndrome (JPS) is a genetic disorder that involves the development of multiple juvenile (hamartomatous) polyps in the stomach, small intestine, colon, and rectum. The age of onset varies from childhood to middle age, though most affected individuals have some polyps by age 20. The risk for gastrointestinal (GI) cancers in JPS families is ~20% by age 35 and approaches ~68% by age 60. Pathogenic variants in the BMPR1A or SMAD4 gene are two known molecular causes of JPS, accounting for 28% and 27% of cases, respectively; at this time, 45% of cases have an unknown etiology.

Disease Overview

Symptoms/Diagnosis

The diagnosis of JPS is established in a proband with any one of the following:

  • >5 juvenilea polyps of the colon or rectum
  • Multiple juvenile polyps of the upper and lower GI tract
  • Any number of juvenile polyps and a family history of juvenile polyposis
  • Identification of a heterozygous pathogenic variant in BMPR1A or SMAD4 gene

The diagnosis of JPS should be suspected in a proband with the following:

  • Anemia, rectal bleeding, or prolapse of rectal polyp
  • >1 juvenile polyp
  • One or more juvenile polyps and a family history of JPS

aJuvenile refers to the histopathology of the polyp, not the age of onset of polyps.

Genetics

Genes

BMPR1A, SMAD4

Incidence

~1/16,000 to 1/100,000 

Inheritance

Autosomal dominant for JPS

De novo rate: ~67%

Penetrance

>90% for polyp development

Test Interpretation

Sensitivity/Specificity

Clinical Sensitivity

BMPR1A: 28%   

  • Sequencing variants: 69-85%
  • Deletion/duplication variants: 15%

Analytical Sensitivity/Specificity

BMPR1A: 99%

Results

Result Variant detected Interpretation

Positive

Pathogenic variant detected

Confirms a diagnosis of JPS

Negative

No pathogenic variant detected

Does not exclude diagnosis of JPS

Uncertain

Variant of unknown clinical significance

Unknown if variant is benign or disease causing

Limitations

  • A negative result does not exclude a diagnosis of JPS.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this individual had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Regulatory region or deep intronic variants
    • Breakpoints of large deletions/duplications
    • Variants in genes other than BMPR1A
  • Large deletions/duplications of exons 7 and 8 in BMPR1A gene may not be detected.
  • The following may not be detected:
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

References

Additional Resources