Submission Details

GREM1 was first reported in relation to autosomal dominant Hereditary mixed polyposis syndrome (HMPS) in 2012 (Jaeger et al., PMID: 22561515), after extensive genomic characterization of 6 Ashkenazi previously described families with HMPS (PMID: 9024286, 10092300, 12696020, 18084292). HMPS describes an autosomal dominantly inherited large-bowel disease characterized by the presence of a mixture of hyperplastic, atypical juvenile and adenomatous polyps that are associated with an increased risk of developing colorectal cancer. Four variants including the Ashkenazi variant leading to partial or complete duplication of GREM1 regulatory regions or coding sequences have been reported in 10 probands in 9 publications (PMIDs: 9024286, 10092300, 12696020, 18084292, 21128281, 22561515, 24586997, 26493165, 29804199) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached (PMIDs: 25992589, 26947005, 28242209, 27984123). Most described patients (14 probands) are carriers of the Ashkenazi founder variant, a 40kb duplication upstream of GREM1 (SCG5-GREM1 dup) (PMID: 22561515). This gene-disease association is also supported by experimental evidence (4 points). The mechanism of pathogenicity is known to be overexpression, which was confirmed in two publications that showed increased GREM1 expression in the normal epithelium of HMPS patients compared with the controls (PMID: 22561515, 26493165). This gene-disease association is also supported by an animal model, showing that GREM1 overexpression recapitulates the HMPS phenotype in the colon and knockout reduces polyp burden and size (PMID: 25419707). In summary, GREM1 is definitively associated with autosomal dominant Hereditary mixed polyposis syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.