Fig. 5

Sites and types of SMAD4 DCVs, protein change and phenotypes, self-made via Microsoft Visio. All 291 variants were collated from the literature. In the top section, SMAD4 gene structure is represented via its exons demarcated by nucleotide numbers. DCVs causing JPS phenotypes have been depicted with lines extending below the diagram in brown (JPS), green (massive gastric polyposis in JPS) and red (GI cancer in JPS). Above the illustrations represent extra-gastrointestinal phenotypes, including HHT (dark red), aortopathy (pink), IBD (purple), Myhre syndrome (dark blue), JIA (light blue), hypertrophic osteoarthropathy (yellow), Ménétrier’s disease (grey) and concurrent GI cancer boxed in bright red. In the bottom section, large deletions and chromosomal translocations are portrayed via solid lines, surrounding the SMAD4 gene, where JPS phenotypes are below, and extra-GI phenotypes are above. c.1245_1248delCAGA (p.Asp415Glufs*20), a highly prevalent DCV, is represented by asterisks (*). Variants of uncertain significance (VUS) are marked with adjacent stars, sourced from JPS registries and case reports, with pathogenicity reviewed by ClinVar