ENG – Juvenile Polyposis Syndrome

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterised by multiple gastrointestinal juvenile polyps and increased colorectal cancer risk. Although ENG (endoglin) has been implicated in overlapping JP-HHT phenotypes when mutated in SMAD4, direct sequencing and dosage analysis across two independent JPS cohorts failed to identify ENG pathogenic variants, arguing against a primary role for ENG in isolated JPS.

1. Clinical Validity Assessment
   – Overall ClinGen classification: Limited. ENG variants were absent in 34 unrelated JPS probands across sequencing and MLPA studies (0/7 probands in JP-HHT combined cohort [PMID:15031030] and 0/27 in comprehensive JPS cohort [PMID:18178612]).

2. Genetic Evidence
   – Inheritance: Autosomal dominant.
   – Segregation: No additional affected relatives with ENG variants.
   – Case series: 34 unrelated JPS probands screened; 0 ENG variants identified ([PMID:15031030], [PMID:18178612]).
   – Variant spectrum: Not applicable for ENG in JPS.

3. Functional Evidence
   – No published functional studies support ENG disruption as a mechanism for juvenile polyp formation or JPS pathogenesis.

4. Conflicting Evidence
   – Robust negative genetic findings: absence of ENG mutations in multiple large JPS cohorts.

5. Integration & Conclusion
   Current evidence does not support ENG as a JPS predisposition gene. Routine ENG testing for isolated JPS is not indicated unless patients present concurrent HHT features. Ongoing research may clarify rare alternative mechanisms, but ENG’s clinical utility in JPS remains limited.

Key Take-home: ENG should not be included in isolated JPS genetic panels in the absence of HHT manifestations.

References

• Gut • 2008 • Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. PMID:18178612
• Lancet • 2004 • A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4. PMID:15031030

Evidence Based Scoring (AI generated)