Juvenile polyposis syndrome: genes and variants

Genes linked to Juvenile polyposis syndrome

• SMAD4: SMAD family member 4

  It forms transcriptional complexes with activated receptor-regulated SMADs and is the central nuclear mediator shared by TGF-beta and BMP pathways. Germline loss-of-function variants cause juvenile polyposis or combined juvenile-polyposis-HHT, while specific gain-of-function variants cause Myhre syndrome.

  18 disease-causing and 585 uncertain variants in SMAD4 are linked to Juvenile polyposis syndrome.

• BMPR1A: Bone morphogenetic protein receptor type-1A

  It transduces BMP signals that regulate epithelial growth, differentiation, and tissue patterning through SMAD proteins and other pathways. Germline loss-of-function variants cause juvenile polyposis syndrome and can substantially increase gastrointestinal cancer risk.

  8 disease-causing and 772 uncertain variants in BMPR1A are linked to Juvenile polyposis syndrome.

Where Juvenile polyposis syndrome variants cluster

• SMAD4 MH2 (positions 323–552): 18 of 18 disease-causing changes, 2.4× more than its size predicts.
• BMPR1A Extracellular (positions 24–152): 4 of 8 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Juvenile polyposis syndrome

Which prediction tools work for Juvenile polyposis syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 89 out of 100
• PolyPhen-2: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Familial thoracic aortic aneurysm and aortic dissection is also caused by SMAD4 variants; they fall in the same places as the Juvenile polyposis syndrome variants (12 disease-causing).

Diseases related to Juvenile polyposis syndrome

• Generalized juvenile polyposis/juvenile polyposis coli, also linked to BMPR1A and SMAD4
• Familial thoracic aortic aneurysm and aortic dissection, also linked to SMAD4
• Pulmonary arterial hypertension, also linked to BMPR1A
• Familial pancreatic carcinoma, also linked to SMAD4
• Hereditary hemorrhagic telangiectasia, also linked to SMAD4
• Carcinoma of pancreas, also linked to SMAD4
• Polyposis syndrome, hereditary mixed, 2, also linked to BMPR1A
• Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, also linked to SMAD4

Frequently asked questions

Which genes are linked to Juvenile polyposis syndrome?

In CATVariant, Juvenile polyposis syndrome is linked to 2 analyzed proteins: SMAD4 (SMAD family member 4) and BMPR1A (Bone morphogenetic protein receptor type-1A).

How many genetic variants are linked to Juvenile polyposis syndrome?

1,454 variants: 26 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,357 are of uncertain significance or have conflicting reports.

Which uncertain variants in Juvenile polyposis syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Juvenile polyposis syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 25 disease-causing and 10 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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