Which SMAD4 gene mutations cause Juvenile Polyposis Syndrome (JPS)?

SMAD4 Mutations Causing Juvenile Polyposis Syndrome

Germline mutations in the SMAD4 gene (also known as SMAD4/DPC4) located on chromosome 18q21.1 cause approximately 20% of Juvenile Polyposis Syndrome cases through autosomal dominant inheritance. 1

Genetic Basis of JPS

SMAD4 is one of two primary genes responsible for JPS:

• SMAD4 mutations account for approximately 20% of JPS cases 2, 3
• BMPR1A mutations account for another 20% of cases 1, 4
• Together, these two genes explain 40-60% of all JPS patients 4, 5
• The remaining 40-60% of cases have no identifiable mutation in either gene 5

Types of SMAD4 Mutations

Both nonsense and missense mutations throughout the SMAD4 gene can cause JPS:

Nonsense Mutations

• Produce 30-60% reduction in BMP signaling activity 3
• Result in truncated, non-functional proteins 6
• Include frameshift mutations such as c.1245_1248del (p.Asp415Glufs) 7
• A novel stop codon mutation at tyrosine 413 in exon 10 has been reported 8

Missense Mutations

• Produce 8-30% reduction in BMP signaling activity 3
• Scattered throughout the gene with no clear hotspot region 9
• Still result in loss of SMAD4 protein expression in polyp tissue 6

Large Deletions

• Whole or partial gene deletions occur but are less frequent 9, 5
• One study found deletions of most of SMAD4 in 1 of 102 probands 5
• Testing must include deletion/duplication analysis, not just sequencing, to detect these mutations 9

Mosaic Variants

• SMAD4 mosaic variants can present with slowly progressive, localized disease 7
• Allele frequencies as low as 23% have been reported in gastric-localized JPS 7

Molecular Mechanism

SMAD4 mutations disrupt the bone morphogenetic protein (BMP) signaling pathway:

• SMAD4 serves as the common intracellular mediator for both TGF-β and BMP pathways 3
• Disruption of BMP signaling is the likely underlying etiology of JPS in SMAD4 mutation carriers 3
• Loss of SMAD4 protein expression occurs in most polyps from mutation carriers, even with missense germline mutations 6
• Polyps from non-SMAD4 JPS cases retain SMAD4 expression, indicating a SMAD4-independent pathway 6

Clinical Implications of SMAD4 Mutations

SMAD4 mutation carriers have distinct clinical features compared to BMPR1A carriers:

Gastrointestinal Manifestations

• 73% develop gastric polyposis (vs. 8% in BMPR1A carriers; p<0.001) 1, 2
• All cases of gastric cancer in JPS cohorts occurred in SMAD4 mutation carriers 1
• Polyps show subtly different morphology with more prominent epithelial component 6

HHT Overlap Syndrome

• 76% of SMAD4 mutation carriers develop clinical features of hereditary hemorrhagic telangiectasia (HHT) 2
• This creates the JPS-HHT overlap syndrome, unique to SMAD4 mutations 1
• Patients require screening for arteriovenous malformations in brain, lungs, and GI tract 1, 2

Cardiovascular Complications

• 38% develop aortopathy regardless of JPS phenotype 1
• 11% risk of valvular heart disease 2
• Mitral valve dysfunction has been reported 1

Surveillance Recommendations Based on Genotype

For confirmed SMAD4 mutations:

• Upper GI tract surveillance every 1-3 years starting at age 18 years (not 25 years as for BMPR1A) 1
• Enhanced gastric cancer surveillance due to 73% gastric polyposis prevalence 2
• Evaluation for HHT features including screening for asymptomatic AVMs 1
• Management in conjunction with specialist HHT center 1

For BMPR1A mutations:

• Upper GI surveillance starting at age 25 years 1
• No HHT screening required 2

Critical Testing Considerations

Comprehensive genetic testing approach is essential:

• Clinical laboratories must perform both sequencing AND deletion/duplication analysis 9
• Sequencing alone will miss whole or partial gene deletions 9
• Never assume negative SMAD4 testing excludes diagnosis if clinical criteria are met 9
• Testing may miss mutations due to technical limitations or mosaicism 9, 7

Common Pitfalls

Do not rely solely on genetic testing for diagnosis:

• Clinical criteria remain the diagnostic foundation (≥5 juvenile polyps in colorectum, juvenile polyps throughout GI tract, or any number with positive family history) 4
• 40-60% of JPS patients have no identifiable mutation 5
• Mosaic variants with low allele frequencies may be missed 7

Distinguish germline from somatic mutations:

• Tumor sequencing can identify somatic mutations or clonal hematopoiesis variants that are not inherited 2
• Germline testing is required for family counseling and cascade testing 9