Table 2.
Tabulated form of SMAD4 variants and associated phenotypes, where families are bolded
| Author & year | Location | Type of mutation | SMAD4 nucleotide mutation | SMAD4 predicted protein change | ClinVar Class | Dx Age | Phenotype | Extra-gastrointestinal phenotypes |
|---|---|---|---|---|---|---|---|---|
| Schwenter et al. (2012) [94] | Exon 9; MH2 domain | Substitution, missense | c.1146C > A | p.(His382Gln) | Unclassified | 1 | JPS with multiple colorectal hamartomatous polyps and duodenal adenomatous polyps | HHT: Epistaxis, telangiectases, lung AVMs |
| Intron 12; MH2 domain | Intronic | c.1447 + 1G > A | p.( =) | Pathogenic | 28 | JPS with FHx, multiple rectal hamartomatous polyps and gastric hyperplastic polyps; diagnosis of CRC | HHT: Epistaxis, telangiectases | |
| Exon 8; MH2 domain | Substitution, missense | c.1082G > T | p.(Arg361Leu) | Pathogenic | 57 | JPS with multiple colorectal hyperplastic polyps and few gastric hamartomatous polyps | HHT: Epistaxis, telangiectases, lung AVMs, cyanosis, digital clubbing, stroke | |
| Exon 8; MH2 domain | Substitution, missense | c.1082G > A | p.(Arg361His) | Pathogenic | 34 | JPS with FHx and multiple colorectal hamartomatous polyps | HHT: Epistaxis, telangiectases, lung AVMs | |
| Exon 11; MH2 domain | Deletion-insertion, frameshift | c.1596_1597delinsT | p.(Leu533Serfs*4) | Pathogenic | 20 | JPS with 10 colorectal polyps and 4 gastric polyps; diagnosis of CRC | HHT: Epistaxis, telangiectases, lung/liver AVMs | |
| Exon 5; Linker domain | Deletion, frameshift | c.728_735del | p.(Gly243Alafs*18) | Pathogenic | 17 | JPS with FHx and 20 colorectal hamartomatous polyps | HHT: Telangiectases, lung AVMs, cyanosis | |
| Exon 9; MH2 domain | Deletion, frameshift | c.1231_1232del | p.(Ser411Leufs*17) | Pathogenic | 22 | JPS with 28 colorectal polyps and multiple gastric hyperplastic polyps | HHT: Epistaxis, telangiectases, cyanosis | |
| Exon 8; MH2 domain | Substitution, miisense | c.1082G > A | p.(Arg361His) | Pathogenic | 27 | JPS with multiple colonic hamartomatous polyps and multiple duodenal adenomatous polyps | HHT: Epistaxis, telangiectases, lung AVMs, stroke, cyanosis | |
| Exon 9; MH2 domain | Deletion, frameshift | c.1231_1232del | p.(Ser411Leufs*17) | Pathogenic | 31 | JPS with FHx | HHT: telangiectases | |
| Exon 5; Linker domain | Substitution, missense | c.746_747delAGinsCC | p.(Gln249Pro) | Unclassified | 10 | JPS with FHx | HHT: Epistaxis, telangiectases | |
| Exon 8; MH2 domain | Substitution, missense | c.1082G > T | p.(Arg361Leu) | Pathogenic | 12 | JPS with FHx and 6 colorectal polyps | HHT: Epistaxis, lung AVMs | |
| Exon 5; Linker domain | Deletion, frameshift | c.728_735del | p.(Gly243Alafs*18) | Pathogenic | N/A | JPS with FHx, multiple colorectal hyperplastic polyps | HHT: Epistaxis | |
| Intron 12; MH2 domain | Intronic | c.1447 + 1G > A | p.( =) | Pathogenic | 10 | JPS with FHx and 9 colorectal juvenile polyps | HHT: Epistaxis, lung AVMs | |
| Ngeow et al. (2013) [77] | Exon 6; SMAD4 activation domain | Deletion | c.(787 + 1_830)_(1139 + 1_1140-1)del | p.? | Unclassified | 59 | Juvenile; adenomatous polyps; diagnosis of CRC | |
| Exon 10; MH2 domain | Deletion | c.1309-?_1659 + ?del | p.? | Unclassified | 17 | Juvenile polyps | ||
| Exon 3; Linker domain | Deletion, frameshift | c.430_431del | p.(Ser144Argfs*7) | Pathogenic | 27 | Juvenile polyps | ||
| Exon 3; Linker domain | Deletion, frameshift | c.430_431del | p.(Ser144Argfs*7) | Pathogenic | 44 | Adenomatous; hamartomatous polyps | ||
| Exon 6; Linker domain | Deletion, frameshift | c.798del | p.(Thr267Profs*69) | Unclassified | 43 | Juvenile; adenomatous polyps | ||
| Exon 6; SMAD4 activation domain | Insertion | c.902dup | p.(Tyr301*) | Unclassified | 47 | Juvenile; hyperplastic polyps | ||
| Exon 8; MH2 domain | Substitution, missense | c.1049 T > A | p.(Val350Asp) | Unclassified | 9 | Juvenile polyps | ||
| Exon 8; MH2 domain | Substitution, missense | c.1087 T > C | p.(Cys363Arg) | Pathogenic | 2 | Juvenile polyps | ||
| Exon 9; MH2 domain | Substitution, nonsense | c.1193G > A | p.(Trp398*) | Pathogenic | 37 | Juvenile; adenomatous polyps; diagnosis of gastric cancer | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1231_1232del | p.(Ser411Leufs*17) | Pathogenic | 21 | Juvenile; adenomatous polyps | HHT: brain & lung arteriovenous malformations | |
| Exon 9; MH2 domain | Deletion, frameshift | c.1231_1232del | p.(Ser411Leufs*17) | Pathogenic | 46 | Juvenile; adenomatous polyps | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 37 | Juvenile; hyperplastic polyps | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 29 | Juvenile polyps | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 32 | Juvenile; adenomatous polyps | Goitre | |
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 24 | Juvenile; hamartomatous polyps | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 39 | Hyperplastic; adenomatous polyps | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1247_1250del | p.(Arg416Lysfs*19) | Unclassified | 44 | Juvenile polyps | HHT: telangiectasia | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1343_1367del | p.(Gln448Leufs*20) | Pathogenic | 45 | Juvenile polyps | ||
| Exon 10; MH2 domain | Deletion, frameshift | c.1343_1367del | p.(Gln448Leufs*20) | Pathogenic | 47 | Juvenile; hyperplastic polyps | ||
| Exon 10; MH2 domain | Deletion, frameshift | c.1343_1367del | p.(Gln448Leufs*20) | Pathogenic | 45 | Inflammatory, adenomatous, hyperplastic, juvenile polyps | ||
| Exon 11; MH2 domain | Substitution, missense | c.1573A > G | p.(Ile525Val) | Conflicting interpretations of pathogenicity | 57 | Adenomatous; hyperplastic polyps | ||
| Exon 11; MH2 domain | Substitution, missense | c.1573A > G | p.(Ile525Val) | Conflicting interpretations of pathogenicity | 50 | Adenomtaous; hyperplastic polyps | ||
| Howe et al. (2004) [48] | Exon 4; Linker domain | Deletion; premature stop codon | c.608del | p.(Pro203Hisfs*38) | Pathogenic | N/A | Familial JPS | |
| Exon 8; MH2 domain | Substitution, missense | c.989A > G | p.(Glu330Gly) | Likely pathogenic | N/A | Familial JPS | ||
| Exon 8; MH2 domain | Deletion; premature stop codon | c.1037del | p.(Pro346Leufs*38) | Pathogenic | N/A | JPS | ||
| Exon 8; MH2 domain | Substitution, missense | c.1054G > A | p.(Gly352Arg) | Pathogenic | N/A | Familial JPS | ||
| Exon 8; MH2 domain | Substitution, missense | c.1081C > G | p.(Arg361Gly) | Likely pathogenic | N/A | Familial JPS | ||
| Exon 8; MH2 domain | Substitution, missense | c.1081C > G | p.(Arg361Gly) | Likely pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Substitution, nonsense | c.1162C > T | p.(Gln388*) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion; premature stop codon | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion; premature stop codon | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion; premature stop codon | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion; premature stop codon | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS | ||
| Exon 10; MH2 domain | Deletion; premature stop codon | c.1343_1365del | p.(Gln448Argfs*38) | Pathogenic | N/A | JPS | ||
| Exon 11; MH2 domain | Substitution, missense | c.1529G > T | p.(Gly510Val) | Pathogenic | N/A | JPS | ||
| Exon 11; MH2 domain | Deletion; premature stop codon | c.1588del | p.(His530Thrfs*7) | Pathogenic | N/A | Familial JPS | ||
| Friedl et al. (2002) [34] | Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 35 | JPS with gastric polyposis & gastrectomy at age 35 | |
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 4 | JPS with nil extracolonic anomalies and FHx | Lennox disease, macrocephaly, severe psychomotoric retardation | |
| Exon 9; MH2 domain | Substituiton, missense | c.1157G > A | p.(Gly386Asp) | Pathogenic/Likely pathogenic | 10 | JPS | HHT features including: pulmonary arteriovenous fistulae, finger clubbing, skeletal thorax abnormalities | |
| Exon 6 | Deletion | c.831_832del | p.(Pro278*) | Pathogenic | 12 | JPS with massive polyposis at 28y with no gastric polyps | Asymptomatic ventricular septal defect | |
| Exon 10; MH2 domain | Substitution; missense | c.1342C > T | p.(Gln448*) | Pathogenic | 12 | JPS | Nil extracolonic features | |
| Exon 11; MH2 domain | Deletion, frameshift | c.1544del | p.(Arg515Asnfs*22) | Pathogenic | 39 | JPS with gastric polyposis, giant gastric folds & gastrectomy at 40y | ||
| Exon 11; MH2 domain | Insertion, frameshift | c.1547_1550dup | p.(Ser517Argfs*11) | Unclassified | 21 | JPS with gastric polyposis at age 36 & gastrectomy at 40y | ||
| Handra-Luca et al. (2005) [41] | Exon 2; MH1 domain | Duplication, frameshift | c.375_381dup | p.(Val128Cysfs*17) | Pathogenic | N/A | JPS | |
| Exon 2; MH1 domain | Duplication, frameshift | c.375_381dup | p.(Val128Cysfs*17) | Pathogenic | N/A | JPS | ||
| Exon 9; MH2 domain | Substitution, nonsense | c.1236C > G | p.(Tyr412*) | Pathogenic | N/A | JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1242del | p.(Asp415Thrfs*21) | Pathogenic | N/A | JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1268del | p.(Gly423Glufs*13) | Pathogenic | N/A | JPS | ||
| Exon 10; MH2 domain | Substitution, nonsense | c.1333C > T | p.(Arg445*) | Pathogenic | N/A | JPS | ||
| Exon 11; MH2 domain | Substitution, missense | c.1571G > T | p.(Trp524Leu) | Pathogenic | N/A | JPS | ||
| Exon 11; MH2 domain | Insertion, frameshift | c.1607dup | p.(Asp537Argfs*40) | Pathogenic | N/A | JPS | ||
| Jelsig et al. (2016) [55] | Exon 9; MH2 domain | Substitution, missense | c.1156G > A | p.(Gly386Ser) | Likely pathogenic | 48 | JPS with FHx, 3 colorectal adenomatous polyps and multiple duodenal polyps | HHT features: epistaxis, telangiectasia, pulmonary and GI AVM, anaemia, stroke |
| Exon 9; MH2 domain | Substitution, missense | c.1156G > A | p.(Gly386Ser) | Likely pathogenic | 27 | Unconfirmed JPS with FHx and 1 caecal inflammatory polyp | HHT features: epistaxis, telangiectasia, pulmonary AVM | |
| Exon 9; MH2 domain | Substitution, missense | c.1156G > A | p.(Gly386Ser) | Likely pathogenic | 16 | Unconfirmed JPS with FHx and 1 colonic juvenile polyp | HHT features: epistaxis, telangiectasia, pulmonary AVM | |
| Exon 8; MH2 domain | Substitution. Missense | c.1081C > T | p.(Arg361Cys) | Pathogenic | 3 | JPS with > 50 juvenile polyps throughout colon, 1 jejunal adenomatous polyp, nil FHx | HHT features: epistaxis, telangiectasia, pulmonary and GI AVM, anaemia, cyanosis, digital clubbing | |
| Exon 8; SMAD4 activation domain | Deletion, frameshift | c.939del | p.(Ile314Phefs*22) | Pathogenic (unconfirmed) | 21 | JPS with < 10 colorectal polyps and several ileal polyps; diagnosis of CRC (21) & gastric cancer (37) | HHT features: epistaxis, telangiectasia, anaemia Passed away at 40y | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1325_1326del | p.(Gln442Leufs*51) | Pathogenic (unconfirmed) | 13 | JPS with FHx and 3 colorectal juvenile polyps | HHT features: epistaxis, telangiectasia, pulmonary AVM, aortopathy (aortic root dilated 5 cm) | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1325_1326del | p.(Gln442Leufs*51) | Pathogenic (unconfirmed) | 17 | JPS with FHx, > 50 juvenile polyps throughout GIT | HHT features: epistaxis, telangiectasia | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1325_1326del | p.(Gln442Leufs*51) | Pathogenic (unconfirmed) | 60 | JPS with FHx, > 50 juvenile polyps throughout GIT; diagnosis of CRC (48) | HHT features: epistaxis, telangiectasia | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1325_1326del | p.(Gln442Leufs*51) | Pathogenic (unconfirmed) | 64 | JPS with FHx, < 10 colorectal juvenile polyps | ||
| Exon 11; MH2 domain | Duplication, frameshift | c.1587dup | p.(His530Thrfs*47) | Pathogenic | 3 | JPS with > 50 juvenile polyps throughout GIT | Anaemia | |
| Exon 1; MH1 domain | Deletion, frameshift | c.1421del | p.(Ser474*) | Pathogenic | 21 | JPS with FHx, > 10–30 colorectal juvenile polyps and several small bowel polyps; diagnosis of CRC (35) | Anaemia | |
| Exon 1; MH1 domain | Deletion, frameshift | c.1421del | p.(Ser474*) | Pathogenic | 43 | JPS with FHx, > 50 colorectal juvenile polyps and several hyperplastic small bowel hyperplastic polyps | ||
| Exon 1; MH1 domain | Deletion, frameshift | c.1421del | p.(Ser474*) | Pathogenic | 15 | JPS with FHx, 10–30 colorectal juvenile polyps | ||
| Exon 5; Linker domain | Insertion, frameshift | c.692dup | p.(Ser232Glnfs*3) | Pathogenic | 18 | JPS with > 50 colorectal juvenile polyps | Anaemia | |
| Woodford-Richens et al. (2000) [108] | Exon 4; Linker domain | Deletion; premature stop codon | c.517_527del | p.(Ser173Thrfs*12) | Pathogenic (unconfirmed) | 12 | JPS with > 50 sigmoid and recal polyps, FHx of CRC | |
| Exon 8; MH2 domain | Substitution, missense | c.1083C > T | p.( =) | Unclassified | 16 | JPS with 4 colorectal polyps, FHx of CRC & JPS | ||
| Exon 11; MH2 domain | Deletion; premature stop codon | c.1564_1565del | p.(Pro522Leufs*4) | Pathogenic | N/A | JPS with FHx, > 100 gastric polyps, 8 colorectal polyps | ||
| Exon 11; MH2 domain | Deletion; premature stop codon | c.1564_1565del | p.(Pro522Leufs*4) | Pathogenic | N/A | JPS with FHx, gastric JPs | ||
| Exon 11; MH2 domain | Deletion | c.189_197del | p.(Asn64_Ala66del) | Pathogenic (unconfirmed) | N/A | JPS with FHx, extensive polyposis throughout GIT, colectomy at 45y | ||
| Exon 11; MH2 domain | Deletion | c.189_197del | p.(Asn64_Ala66del) | Pathogenic (unconfirmed) | N/A | JPS with FHx, colorectal juvenile polyps, coloectomy at 21y | ||
| Exon 10; MH2 domain | Substitution; nonsense | c.1333C > T | p.(Arg445*) | Pathogenic | 39 | JPS with FHx, colonic polyps with tubular adenoma | ||
| Exon 10; MH2 domain | Substitution; nonsense | c.1333C > T | p.(Arg445*) | Pathogenic | 6 | JPS with FHx, > 100 juvenile polyps throughout GIT | ||
| Aretz et al. (2007) [4] | Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 41 | Familial JPS with multiple juvenile colonic and gastric polyps | |
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 4 | Familial JPS with numerous juvenile, hyperplastic and adenomatous colonic polyps | ||
| Exon 9; MH2 domain | Substitution, missense | c.1157G > A | p.(Gly386Asp) | Pathogenic/Likely pathogenic | 10 | JPS with > 50 colonic juvenile polyps | ||
| Exon 6; SMAD4 activation domain | Deletion | c.831_832del | p.(Pro278*) | Pathogenic | 12 | Familial JPS with > 50 colonic and gastric juvenile, hyperplastic polyps | ||
| Exon 6–11 | Deletion | c.788-?_1659 + ?del | p.? | Unclassified | 12 | Familial JPS with numerous colonic and gastric juvenile/adenomatous polyps | ||
| Exon 10; MH2 domain | Substitution, nonsense | c.1342C > T | p.(Gln448*) | Pathogenic | 12 | JPS with massive juvenile and adenomatous colonic polyps | ||
| Exon 11; MH2 domain | Deletion | c.(?_-17093)_(*6575_?)del | p.0 | Pathogenic (unconfirmed) | 18 | JPS with > 100 juvenile, adenomatous, hyperplastic colonic polyps | ||
| Exon 11; MH2 domain | Deletion, frameshift | c.1544del | p.(Arg515Asnfs*22) | Pathogenic | 40 | JPS with multiple juvenile colonic and gastric polyps | ||
| Exon 11; MH2 domain | Duplication, frameshift | c.1547_1550dup | p.(Ser517Argfs*11) | Pathogenic (unconfirmed) | 24 | Familial JPS with numerous juvenile and adenomatous colonic/gastric polyps | ||
| Exon 8; MH2 domain | Substitution | c.1139G > A | p.(Arg380Lys) | Likely pathogenic | 38 | JPS with 10 adenomatous colonic polyps with hundreds of gastric juvenile polyps | ||
| Exon 11; MH2 domain | Deletion | c.(?_-17093)_(*6575_?)del | p.0 | Pathogenic (unconfirmed) | 33 | JPS with massive juvenile and adenomatous colonic polyps | ||
| Exon 3; Linker domain | Substitution | c.425-6A > G | p.( =) | Uncertain significance | 10 | Familial JPS with numerous colonic/gastric polyps | ||
| Exon 11; MH2 domain | Deletion | c.(?_-17093)_(*6575_?)del | p.0 | Pathogenic (unconfirmed) | 45 | Familial JPS with > 30 juvenile, adenomatous and inflammatory colonic polyps and pronounced gastric polyps | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 48 | Familial JPS with multiple colonic juvenile polyps and pronounced gastric polyposis | ||
| Exon 10; MH2 domain | Deletion, frameshift | c.1421del | p.(Ser474*) | Pathogenic | 54 | Familial JPS with several juvenile colonic and gastric polyps | ||
| Exon 5–11 | Deletion | c.668-?_1659 + ?del | p.? | Unclassified | 50 | JPS with massive juvenile gastric polyposis with 2 colonic polyps | ||
| Exon 3; Linker domain | Substitution, nonsense | c.437 T > A | p.(Leu146*) | Pathogenic | 48 | Familial JPS with multiple juvenile gastric polyps and > 5 colonic polyps | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 23 | JPS with > 20 colonic juvenile and inflammatory polyps | ||
| Exon 8; MH2 domain | Substitution, missense | c.1087 T > C | p.(Cys363Arg) | Pathogenic | 5 | JPS with multiple colonic polyps | ||
| Exon 8; MH2 domain | Substitution, missense | c.1082G > A | p.(Arg361His) | Pathogenic | 11 | JPS with > 50 colonic juvenile polyps | ||
| Exon 8; MH2 domain | Substitution, missense | c.1081C > T | p.(Arg361Cys) | Pathogenic | 3 | JPS with > 30 colonic juvenile polyps | ||
| Exon 11; MH2 domain | Deletion | c.(?_-17093)_(*6575_?)del | p.0 | Pathogenic (unconfirmed) | 12 | JPS with massive juvenile colonic polyposis | ||
| Exon 2; MH1 domain | Substitution, nonsense | c.403C > T | p.(Arg135*) | Pathogenic | 48 | JPS with > 20 colonic juvenile polyps and pronounced gastric polyposis | ||
| Gallione et al. (2004) [36] | Exon 11; MH2 domain | Deletion | c.1612_1625del | p.(Glu538Hisfs*34) | Pathogenic | 41 | Caecal juvenile polyps, GI cancer | HHT features: telangiectasia, epistaxis, pulmonary and liver AVMs |
| Exon 11; MH2 domain | Deletion | c.1612_1625del | p.(Glu538Hisfs*34) | Pathogenic | 8 | Colorectal juvenile polyps | HHT features: telangiectasia, epistaxis, anaemia | |
| Exon 8; MH2 domain | Substitution, missense | c.1054G > A | p.(Gly352Arg) | Pathogenic | 9 | Colorectal juvenile polyps | HHT features: telangiectasia, pulmonary AVM, anaemia, digital clubbing | |
| Exon 8; MH2 domain | Substitution, missense | c.1054G > A | p.(Gly352Arg) | Pathogenic | 5 | Colorectal juvenile polyps, GI cancer | HHT features: pulmonary AVM, anaemia, digital clubbing, stroke with intracranial bleed | |
| Exon 8; MH2 domain | Substitution, missense | c.1054G > A | p.(Gly352Arg) | Pathogenic | 3 | Colorectal juvenile polyps | HHT features: liver AVM, anaemia, digital clubbing | |
| Exon 11; MH2 domain | Substitution, missense | c.1598 T > G | p.(Leu533Arg) | Pathogenic | 15 | Colorectal juvenile polyps | HHT features telangiectases, epistaxis, anaemia | |
| Exon 11; MH2 domain | Substitution, missense | c.1598 T > G | p.(Leu533Arg) | Pathogenic | 14 | Colorectal juvenile polyps | HHT features: telangiectases, epistaxis, anaemia | |
| Exon 11; MH2 domain | Substitution, missense | c.1598 T > G | p.(Leu533Arg) | Pathogenic | 3 | Colorectal juvenile polyps | HHT features: telangiectases, epistaxis, anaemia, digital clubbing, pulmonary & liver AVM | |
| Exon 11; MH2 domain | Substitution, missense | c.1598 T > G | p.(Leu533Arg) | Pathogenic | N/A | Not examined | HHT features: pulmonary AVM, anaemia | |
| Exon 8; MH2 domain | Substitution, missense | c.1081C > G | p.(Arg361Gly) | Likely pathogenic | 14 | Colorectal and gastric juvenile polyps | HHT features: telangiectases, epistaxis, anaemia | |
| Exon 9; MH2 domain | Substitution, missense | c.1157G > A | p.(Gly386Asp) | Pathogenic/Likely pathogenic | 10 | Colorectal & duodenal juvenile polyps, GI cancer | HHT features: anaemia, pulmonary AVM, telangiectasia, epistaxis, stroke, digital clubbing, stroke, intracranial bleed | |
| Exon 9; MH2 domain | Substitution, missense | c.1157G > A | p.(Gly386Asp) | Pathogenic/Likely pathogenic | 4 | Colorectal juvenile polyps | HHT features: anaemia, pulmonary AVM, digital clubbing, cyanosis | |
| Exon 11; MH2 domain | Deletion | c.1594del | p.(Ala532Profs*5) | Pathogenic | 11 | Colorectal juvenile polyps | HHT features: anaemia, telangiectases, epistaxis | |
| Exon 11; MH2 domain | Substitution, nonsense | c.1600C > T | p.(Gln534*) | Pathogenic | 10 | Upper GI especially duodenal juvenile polyps, GI cancer | HHT features: liver AVM, epistaxis, digital clubbing, mild seizures | |
| Gallione et al. (2006) [37] | Exon 11; MH2 domain | Deletion-insertion Frameshift mutation | c.1596_1597delinsT | p.(Leu533Serfs*4) | Pathogenic | 37 | Multiple colonic juvenile polyps with GI bleeding | HHT features: telangiectases, epistaxis, AVMs in the lung and GIT, nil FHx |
| Exon 8; MH2 domain | Substitution, missense | c.1081C > T | p.(Arg361Cys) | Pathogenic | 39 | Unclassified regarding JP symptoms | HHT features: telangiectases, epistaxis, pulmonary AVM, liver shunts nil FHx | |
| Exon 8; MH2 domain | Substitution, missense | c.1081C > T | p.(Arg361Cys) | Pathogenic | 13 | Mulitple hamartomatous polyps found in the ascending colon + duodenum; Signet ring cell type CRC (caecum) | HHT features: telangiectases, epistaxis, hepatic AVM, anaemia | |
| Hattem et al. (2008) [104] | Exon 8; MH2 domain | Substitution, missense | c.970 T > C | p.(Cys324Arg) | Uncertain significance | N/A | JPS | (Juvenile polyposis registry) |
| Exon 8; MH2 domain | Substitution, missense | c.989A > G | p.(Glu330Gly) | Likely pathogenic | N/A | JPS | ||
| Exon 8; MH2 domain | Deletion – > frameshift | c.971del | p.(Cys324Phefs*12) | Pathogenic | N/A | JPS | ||
| Exon 9; MH2 domain | Substitution, nonsense | c.1193G > A | p.(Trp398*) | Pathogenic | N/A | JPS | ||
| Exon 10; MH2 domain | Deletion – > frameshift | c.1411_1435del | p.(Gly471Leufs*25) | Pathogenic | N/A | JPS | ||
| Exon 11; MH2 domain | Duplication – > frameshift | c.1586_1587dup | p.(His530Tyrfs*8) | Pathogenic | N/A | JPS | ||
| Exon 1–11 | Hemizygous deletion | c.(?_-538)_(*6575_?)del | p.0 | Pathogenic (unconfirmed) | N/A | JPS | ||
| Pyatt et al. (2006) [86] | Exon 2; MH1 domain | Substitution, missense | c.403C > T | p.(Arg135*) | Pathogenic | 35 | > 20 juvenile polyps | |
| Exon 3; Linker domain | Deletion, premature stop codon | c.430_431del | p.(Ser144Argfs*7) | Pathogenic | Infancy | > 5 juvenile polyps in rectum, stomach | ||
| Exon 5; Linker domain | Insertion, premature stop codon | c.731_732insGCCC | p.(Gln245Profs*20) | Pathogenic (unconfirmed) | 9 | > 140 juvenile polyps in colon, terminal ileum | ||
| Exon 7; Linker domain | Duplication, premature stop codon | c.925_928dup | p.(Phe310Cysfs*13) | Pathogenic | 17 | > 10 juvenile polyps in transverse, descending, sigmoid & rectum | ||
| Exon 8; MH2 domain | Insertion, premature stop codon | c.982dup | p.(Tyr328Leufs*3) | Pathogenic | 9.5 | > 9 juvenile polyps—hepatic flexure, rectum | ||
| Exon 8; MH2 domain | Deletion | c.1088_1090del | p.(Cys363del) | Pathogenic | 11 | Colonic polyps | HHT symptoms | |
| Exon 8; MH2 domain | Substitution, missense | c.1091 T > G | p.(Leu364Trp) | Pathogenic | 2.5 | > 15 juvenile colonic polyps | ||
| Exon 8; MH2 domain | Deletion, premature stop codon | c.1113del | p.(His371Glnfs*13) | Pathogenic | 33 | Multiple juvenile polyps in colon and stomach | ||
| Exon 9; MH2 domain | Deletion, premature stop codon | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 10 | > 6 juvenile polyps in sigmoid | ||
| Exon 9; MH2 domain | Deletion, premature stop codon | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 21 | Innumerable juvenile polyps in colon & stomach | ||
| Exon 10; MH2 domain | Deletion, premature stop codon | c.1361_1364del | p.(Ala454Glufs*21) | Pathogenic | 23 | > 20 juvenile polyps in caecum, ascending, descending, sigmoid | ||
| Intron 10 | Intronic | c.1308 + 1G > A | p.( =) | Pathogenic/Likely pathogenic | 30 | > 15 juvenile polyps with focal adenomatous changes in the colon | ||
| Exon 11; MH2 domain | Deletion, premature stop codon | c.1596del | p.(Leu533Serfs*4) | Pathogenic (unconfirmed) | 7 | Colectomy at 7yo | HHT symptoms | |
| O'Malley et al. (2011) [80] | Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: telangiectasia, pulmonary AVM |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: FHx, telangiectasia, cranial AVM | |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: FHx. GI AVM | |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: telangiectasia, epistaxis, asthma | |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: telangiectasia, epistaxis, pulmnary AVM, asthma | |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: FHx, telangiectasia, epistaxis, pulmonary AVM, asthma | |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: epistaxis, cranial/pulmonary AVM, asthma | |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | JPS | HHT features: FHx, epistaxis, pulmonary AVM, asthma | |
| Exon 3/4; Linker domain | Substitution; missense | c.1363C > A | p.(Gln455Lys) | Unclassified | N/A | JPS | HHT features: FHx, pulmonary AVM, asthma | |
| Exon 3/4; Linker domain | Substitution; missense | c.1363C > A | p.(Gln455Lys) | Unclassified | N/A | JPS | HHT features: telangiectasia, epistaxis, pulmonary AVM | |
| Exon 2/3; MH1/Linker | Deletion | c.430_431del | p.(Ser144Argfs*7) | Pathogenic | N/A | JPS | HHT features: N/A | |
| Exon 8; MH2 domain | Duplication | c.956-?_1139 + ?dup | p.? | Unclassified | N/A | JPS | HHT features: telangiectasia, epistaxis, cranial/pulmonary AVM, asthma | |
| Exon 8; MH2 domain | Duplication | c.956-?_1139 + ?dup | p.? | Unclassified | N/A | JPS | HHT features: FHx, telangiectasia, pulmonary AVM | |
| Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | N/A | JPS | HHT features: telangiectasia, epistaxis, pulmonary AVM, asthma | |
| Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | N/A | JPS | HHT features: FHx, telangiectasia, epistaxis, pulmonary AVM | |
| Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | N/A | JPS | HHT features: FHx, telangiectasia, epistaxis, pulmonary AVM, asthma | |
| Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | N/A | JPS | HHT features: FHx, epistaxis, cranial/pulmonary AVM | |
| Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | N/A | JPS | HHT features: FHx, epistaxis, pulmonary AVM, asthma | |
| Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | N/A | JPS | HHT features: FHx, epistaxis | |
| Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | N/A | JPS | HHT features: FHx, epistaxis, GI AVM | |
| Exon 9; MH2 domain | Unclassified | Exon 9 | 0 | Unclassified | N/A | JPS | HHT features: telangiectasia, epistaxis, pulmonary/cranial/GI AVM | |
| Gallione et al. (2010) [35] | Exon 2; MH1 domain | Substitution, nonsense | c.302G > A | p.(Trp101*) | Pathogenic | 13.5 | Colonic and rectal juvenile polyps; JPS | HHT features: pulmonary AVM. Other: Williams syndrome, dental caries, acanthosis nigricans |
| Exon 5; Linker domain | Duplication, frameshift | c.692dup | p.(Ser232Glnfs*3) | Pathogenic | 22 | Colonic, duodenal and gastric juvenile polyps; JPS with FHx | HHT features: pulmonary AVM, FHx of HHT Other: UC, mild HTN | |
| Exon 8; MH2 domain | Substitution, missense | c.988G > A | p.(Glu330Lys) | Pathogenic | 6.5 | Colonic and caecal juvenile polyps; JPS with FHx | HHT features: FHx, anaemia, epistaxis | |
| Exon 8; MH2 domain | Substitution, missense | c.1055G > A | p.(Gly352Glu) | Pathogenic | 65 | Colonic, duodenal and gastric juvenile polyps; JPS | HHT features: anaemia, pulmonary AVM, telangiectasia, epistaxis | |
| Exon 8; MH2 domain | Substitution, missense | c.1081C > T | p.(Arg361Cys) | Pathogenic | 9 | Colonic and gastric juvenile polyps; JPS | HHT features: anaemia, pulmonary AVM, telangiectasia, epistaxis, asthma | |
| Exon 8; MH2 domain | Substitution, missense | c.1081C > T | p.(Arg361Cys) | Pathogenic | 17 | GI juvenile polyps; JPS with FHx | HHT features: pulmonary AVM, epistaxis, digital clubbing, FHx of HHT, stroke | |
| Exon 8; MH2 domain | Substitution, missense | c.1082G > T | p.(Arg361Leu) | Pathogenic | 34 | Colonic and rectal juvenile polyps; JPS with FHx of CRC (34y) | HHT features: pulmonary AVM, telangiectasia, epistaxis, digital clubbing, FHx of HHT; other: polycythaemia, dental caries, brain abscess (35y) | |
| Exon 8; MH2 domain | Substitution, missense | c.1082G > A | p.(Arg361His) | Pathogenic | 35 | Colonic and caecal juvenile polyps; JPS with FHx of CRC (35y) | HHT features: anaemia, pulmonary AVM, telangiectasia, epistaxis; Other: hysterectomy/oophorectomy (36), died of metastatic CRC | |
| Exon 8; MH2 domain | Substitution, missense | c.1091 T > G | p.(Leu364Trp) | Pathogenic | 2.5 | Colorectal and caecal juvenile polyps; JPS with FHx | HHT features: pulmonary and hepatic AVM, epistaxis, digital clubbing, FHx of HHT; Other: thrombosis, FTT | |
| Exon 8; MH2 domain | Deletion, frameshift | c.1102_1103del | p.(Ser368Glnfs*9) | Pathogenic | 17 | Colonic juvenile polyps; JPS | HHT features: anaemia, telangiectases, epistaxis | |
| Exon 9; MH2 domain | Substitution, missense | c.1148 T > A | p.(Ile383Lys) | Conflicting interpretations of pathogenicity | 21 | Colonic, ileal, duodenal juvenile polyps; JPS | HHT features: anaemia, pulmonary AVM, telangiectasia, epistaxis, digital clubbing; other: cyanosis, MV prolapse, asthma | |
| Exon 9; MH2 domain | Substitution, missense | c.1157G > A | p.(Gly386Asp) | Pathogenic/Likely pathogenic | 15 | Colonic juvenile polyps; JPS with CRC (20y) | HHT features: anaemia, pulmonary AVM, telangiectasia, epistaxis | |
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 44 | Colonic juvenile polyps; JPS with FHx | HHT features: pulmonary AVM, telangiectasia, epistaxis, FHx of HHT | |
| Exon 11; MH2 domain | Duplication, frameshift | c.1586_1587dup | p.(His530Tyrfs*8) | Pathogenic | 3 | Colorectal juvenile polyps; JPS | HHT features: anaemia, pulmonary and cerebral AVM, telangiectasia, epistaxis, digital clubbing; other: asthma | |
| Exon 11; MH2 domain | Substitution, missense | c.1598 T > C | p.(Leu533Pro) | Pathogenic | 36 | Colonic juvenile polyps; JPS | HHT features: anaemia, pulmonary AVM, telangiectasia, epistaxis, digital clubbing, FHx of HHT | |
| Duan et al. (2019) [29] | Exon 2; MH1 domain | Substitution, missense | c.290G > T | p.(Arg97Leu) | Conflicting interpretations of pathogenicity | 24 | Nil JPS, HHT, Myhre syndrome | Heritable thoracic aortic disease (HTAD)—ascending aortic dissection at 24y, passed away with ovarian cancer at 44y |
| Exon 2; MH1 domain | Substitution, missense | c.290G > T | p.(Arg97Leu) | Conflicting interpretations of pathogenicity | 41 | Nil JPS, HHT, Myhre syndrome | HTAD—ascending aortic aneurysm at 41y with bicuspid aortic valve | |
| Exon 1; MH1 domain | Substitution, missense | c.70A > G | p.(Met24Val) | Uncertain significance | 37 | Nil JPS, HHT, Myhre syndrome | Type A aortic dissection at 37y; DNA samples | |
| Exon 5; Linker domain | Substitution, missense | c.736C > A | p.(Pro246Thr) | Uncertain significance | 54 | Nil JPS, HHT, Myhre syndrome | Type A aortic dissection at 54y | |
| Rohlin et al. (2017) [88] | Exon 8; MH2 domain | Deletion, frameshift | c.1110_1114del | p.(His371Aspfs*5) | Pathogenic (unconfirmed) | N/A | Unexplained adenomatous polyposis Pathogenic variant for CRC | |
| Calva-Cerqueira et al. (2009) [20] | Exon 2; MH1 domain | Insertion, frameshift | c.373_374insAT | p.(Ser125Asnfs*5) | Pathogenic | N/A | Sporadic JPS | |
| Exon 4; Linker domain | Deletion, frameshift | c.608del | p.(Pro203Hisfs*38) | Pathogenic | N/A | Familial JPS | ||
| Exon 8; MH2 domain | Substitution, missense | c.989A > G | p.(Glu330Gly) | Likely pathogenic | N/A | Sporadic JPS | ||
| Exon 8; MH2 domain | Substitution, gene deletion | c.1139 + 1G > A | p.( =) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 8; MH2 domain | Deletion, frameshift | c.1037del | p.(Pro346Leufs*38) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 8; MH2 domain | Substitution, missense | c.1054G > A | p.(Gly352Arg) | Pathogenic | N/A | Familial JPS | ||
| Exon 8; MH2 domain | Substitution, missense | c.1081C > A | p.(Arg361Ser) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 8; MH2 domain | Substitution, missense | c.1081C > G | p.(Arg361Gly) | Likely pathogenic | N/A | Sporadic JPS | ||
| Exon 9; MH2 domain | Substitution, nonsense | c.1162C > T | p.(Gln388*) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 9; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 9; MH2 domain | Substitution, missense | c.1321C > A | p.(Arg441Ser) | Unclassified | N/A | Familial JPS | ||
| Exon 10; MH2 domain | Deletion, frameshift | c.1343_1365del | p.(Gln448Argfs*38) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 11; MH2 domain | Substitution, missense | c.1525 T > A | p.(Trp509Arg) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 11; MH2 domain | Substitution, missense | c.1529G > T | p.(Gly510Val) | Pathogenic | N/A | Sporadic JPS | ||
| Exon 11; MH2 domain | Deletion, frameshift | c.1588del | p.(His530Thrfs*7) | Pathogenic | N/A | Sporadic JPS | ||
| Sayed et al. (2002) [91] | Exon 4; Linker domain | Deletion | c.608del | p.(Pro203Hisfs*38) | Pathogenic | N/A | Familial JPS, > 10 LGI polyps, FHx of GI cancer, nil upper GI involvement | |
| Exon 8; MH2 domain | Substitution | c.989A > G | p.(Glu330Gly) | Likely pathogenic | N/A | Familial JPS, FHx of GI cancer | ||
| Exon 8; MH2 domain | Deletion | c.1037del | p.(Pro346Leufs*38) | Pathogenic | N/A | Unclassified | ||
| Exon 8; MH2 domain | Substitution | c.1054G > A | p.(Gly352Arg) | Pathogenic | N/A | Familial JPS, > 10 LGI polyps, FHx GI cancer, upper GI involvement | ||
| Exon 9; MH2 domain | Substitution | c.1162C > T | p.(Gln388*) | Pathogenic | N/A | Familial JPS, > 10 LGI polyps, FHx GI cancer, upper GI involvement | ||
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS, > 10 LGI polyps, FHx GI cancer, upper GI involvement | ||
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS, > 10 LGI polyps, FHx GI cancer, upper GI involvement | ||
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS, FHx GI cancer, nil upper GI involvement | ||
| Exon 11; MH2 domain | Deletion | c.1588del | p.(His530Thrfs*7) | Pathogenic | N/A | Familial JPS, > 10 LGI polyps, FHx GI cancer, nil upper GI involvement | ||
| Kim et al. (2000) [62] | Exon 8; MH2 domain | Substitution; missense | c.1082G > A | p.(Arg361His) | Pathogenic | 16 | Familial JPS with FHx, > 20 colorectal juvenile polyps, with polypectomy | |
| Exon 9; MH2 domain | Substitution; nonsense | c.1162C > T | p.(Gln388*) | Pathogenic | 20 | JPS with nil FHx, many small bowel, colorectal juvenile polyps, with total colectomy with ileorectal anastomosis | ||
| Exon 9; MH2 domain | Substitution; missense | c.1168G > A | p.(Glu390Lys) | Pathogenic | 16 | JPS with nil FHx, 28 colorectal juvenile polyps, with restorative proctocolectomy with ileal pouch-anal anastomosis | ||
| Roth et al. (1999) [89] | Exon 4; Linker domain | Substitution; nonsense | c.533C > G | p.(Ser178*) | Pathogenic | 38 | Sporadic JPS with 10–50 juvenile polyps in stomach, small & large intestines | Congenital panhypopituitarism |
| Exon 9; MH2 domain | Substitution; missense | c.1058A > C | p.(Tyr353Ser) | Pathogenic | N/A | Familial JPS with FHx, < 10 colonic juvenile polyps; Colorectal (42) & pancreatic carcinoma (50) | ||
| Exon 9; MH2 domain | Substitution; missense | c.1058A > C | p.(Tyr353Ser) | Pathogenic | N/A | Familial JPS with FHx, 10–50 colonic juvenile polyps | ||
| Exon 10; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS with FHx, < 10 colonic juvenile polyps | Adenomatous changes | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS with FHx, > 50 colonic juvenile polyps | Adenomatous changes | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS with FHx, > 50 colonic juvenile polyps; Colorectal carcinoma (30y) | Adenomatous changes | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS with FHx, < 10 colonic juvenile polyps | Adenomatous changes | |
| Exon 10; MH2 domain | Deletion, frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Familial JPS with FHx, 10–50 juvenile polyps in stomach, small and large intestine | Adenomatous changes | |
| Friedl et al. (1999) [33] | Exon 8; MH2 domain | Deletion; frameshift | c.831_832del | p.(Pro278*) | Pathogenic | 12 | Familial JP with > 50 juvenile polyps by age 12. Severe gastric polyposis at 28y. FHx of CRC (father, several paternal relatives) | |
| Exon 10; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 35 | Familial JP with multiple juvenile polyps in colon and stomach (35-40y), colonic complications less pronounced. Massive gastric polyposis, requiring partial or total gastrectomy in family members | ||
| Exon 10; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 4 | Familial JP with multiple juvenile colonic polyps at age 4-5y in 2 brothers | ||
| Howe et al. (1998) [47] | Exon 6; SMAD4 activation domain | Deletion; frameshift | c.815_820del | p.(Arg272_Ala274delinsThr) | Pathogenic (unconfirmed) | 6 | 30–40 colonic juvenile polyps (aged 6) with no FHx of JP | |
| Exon 8; MH2 domain | Deletion; frameshift | c.1170_1171del | p.(Cys391*) | Pathogenic (unconfirmed) | N/A | Colonic and gastric juvenile polyps with FHx of GI symptoms | ||
| Exon 9; MH2 domain | Deletion; frameshift | c.1432_1434del | p.(Ile478del) | Pathogenic (unconfirmed) | N/A | JPS | ||
| Exon 9; MH2 domain | Deletion; frameshift | c.1432_1434del | p.(Ile478del) | Pathogenic (unconfirmed) | N/A | JPS | ||
| Exon 9; MH2 domain | Deletion; frameshift | c.1432_1434del | p.(Ile478del) | Pathogenic (unconfirmed) | N/A | JPS | ||
| Wain et al. (2014) [106] | Exon 2; MH1 domain | Deletion; frameshift | c.263_267del | p.(Lys88Ilefs*14) | Pathogenic (unconfirmed) | N/A | Mutation shared by 3 families including 6 individuals | |
| Exon 2; MH1 domain | Deletion; frameshift | c.373_374insAT | p.(Ser125Asnfs*5) | Pathogenic | N/A | 1 reported with JP phenotype | ||
| Exon 5; Linker domain | Deletion; frameshift | c.692dup | p.(Ser232Glnfs*3) | Pathogenic | N/A | 3 individuals shared this mutation, reported with JP phenotype & JP-HHT | ||
| Exon 5; Linker domain | Deletion; frameshift | c.759del | p.(Phe253Leufs*83) | Pathogenic (unconfirmed) | N/A | 1 | ||
| N/A | Intronic | c.1308 + 1G > A | p.( =) | Unclassified | N/A | 5 unrelated individuals shared this genotype | ||
| Exon 8; MH2 domain | Substitution; missense | c.1081C > T | p.(Arg361Cys) | Unclassified | N/A | 2 individuals with same mutation, where one was reported with JP and the other JP-HHT | ||
| Exon 8; MH2 domain | Deletion; frameshift | c.1081del | p.(Arg361Alafs*23) | Pathogenic (unconfirmed) | N/A | 1 | ||
| Exon 8; MH2 domain | Substitution; missense | c.1082G > A | p.(Arg361His) | Pathogenic | N/A | 3 individuals shared this mutation, some reported with JP, and others JP-HHT | ||
| Exon 8; MH2 domain | Substitution; nonsense | c.1096C > T | p.(Gln366*) | Pathogenic | N/A | 1 | ||
| Exon 9; MH2 domain | Substitution; nonsense | c.1193G > A | p.(Trp398*) | Pathogenic | N/A | 1 individual reported with JP | ||
| Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | Mutation shared by 4 families in 6 individuals | ||
| Exon 10; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | N/A | 2 unrelated individuals shared this phenotype | ||
| Exon 11; MH2 domain | Substitution; missense | c.1525 T > A | p.(Trp509Arg) | Pathogenic | N/A | 1 individual reported with JP | ||
| Exon 1–11 | Multi-exonic deletion | c.(?_-538)_(1447 + 1_1448-1)del | p.? | Unclassified | N/A | 1 | ||
| CASE REPORTS | ||||||||
| Sakurai et al. (2021) [90] | Exon 5; Linker domain | Substitution; nonsense | c.502G > T | p.(Gly168*) | Likely pathogenic | 49 | Multiple gastric hyperplastic polyps in all parts of the stomach. Gastric juvenile polyposis with adenocarcinoma treated with laparoscopic total gastrectomy | Presented with anaemia, Hx of appendicectomy at 7, FHx of breast cancer, nil FHx of GI cancer or polyposis |
| Poaty et al. (2021) [84] | Exon 9; MH2 domain | Deletion; frameshift | c.1231_1232del | p.(Ser411Leufs*17) | Pathogenic | 25 | > 100 colonic juvenile polyps, underwent subtotal colectomy, FHx of colon cancer (paternal) | Presented with long medical history of recurrent diarrhoea since 15, associated with loss of weight, mild abdominal pain, rectal bleeding, anaemia, bloating and intestinal occlusion |
| Kopiec et al. (2021) [63] | Exon 8; MH2 domain | Substitution; missense | c.1082G > A | p.(Arg361His) | Pathogenic | 11 | ¬40 juvenile polyps, mostly colorectal, but also gastric and small bowel, with JPS diagnosis. FHx of JPS and HHT (maternal) | Features of HHT: telangiectasias, cyanosis of lips/nails, pulmonary AVM, pulmonary artery dilatation and tricuspid valve regurgitation, epistaxis; Initially presented with rectal bleeding (first time when 4), recurrent nasal bleeding |
| Kang et al. (2021) [59] | Exon 9; MH2 domain | Deletion; frameshift | c.1146_1163del | p.(His382_Val387del) | Pathogenic | 7 | 30–50 colonic juvenile polyps observed with annual polypectomy, ¬10 jejunal polyps and telangiectases | Features of HHT: telangiectasias, pulmonary AVM, epistaxis, digital clubbing |
| Hashimoto et al. (2020) [42] | Exon 8; MH2 domain | Substitution; missense | c.1081C > T | p.(Arg361Cys) | Pathogenic | 9 | Multiple colonic & numerous gastric juvenile polyps with FHx of maternal colonic & stomach polyps with early gastric cancer + symptoms of HHT | Features of HHT: epistaxis, telangiectasias, pulmonary, liver and mammary gland AVM, anaemia |
| Faisal et al. (2020) [31] | Not mentioned | Not mentioned | Not mentioned | 0 | #N/A | 7 | > 20 colonic, gastric and small bowel juvenile polyps. Diagnosed with small bowel carcinoma at 24, passed away from metastatic disease | Hx of IBD on immunosuppressants (increased cancer risk) |
| Chang et al. (2020) [22] | Not mentioned | Not mentioned | Not mentioned | 0 | #N/A | 32 | > 100 colonic, small bowel and gastric juvenile polyps, large fungating gastric mass (benign hyperplastic tissue) with no known family history. Underwent total gastrectomy | Presented with severe symptomatic anaemia |
| Aagaard et al. (2020) [1] | Intron b/n exons 5–6 Linker/MH2 domain (breakpoint) | Chromosomal translocation via chromosomal analysis | t(1;18)(p36.1;q21.1) | p.? | Pathogenic (unconfirmed) | N/A | 2 juvenile polyps (gastric) with strong FHx of JPS & HHT (brother: multiple JPs, cousin: multiple JPs, CRC at 33y) | HHT features: epistaxis, telangiectasia, FHx of HHT (mother & brother with epistaxis, telangiectasia, PAVM) |
| Inoguchi et al. (2019) [50] | Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 40 | Multiple colonic juvenile polyps with substantial gastric polyposis with FHx of gastric cancer | HHT features: epistaxis, telangiectasia, pulmonary AVM, clubbing; other: aortic aneurysm, fatty degeneration of LV, coronary aneurysm |
| Leon et al. (2019) [28] | Exon 9; MH2 domain | Duplication | c.1213dup | p.(His405Profs*24) | Pathogenic (unconfirmed) | 24 | > 10 colonic juvenile hyperplastic polyps with massive juvenile polyposis of the stomach with high grade dysplasia with total gastrectomy (2017), with FHx of JPS | HHT features: epistaxis, pulmonary AVM |
| Duplication | c.1213dup | p.(His405Profs*24) | Pathogenic (unconfirmed) | 47 | > 10 colonic juvenile polyps of adenomatous and hyperplastic nature with massive gastric polyposis with subtotal gastrectomy, with FHx of JPS | HHT features: epistaxis in adolescent years | ||
| Duplication | c.1213dup | p.(His405Profs*24) | Pathogenic (unconfirmed) | 23 | > 20 colonic juvenile hamartomatous polyps, as well as massive gastric polyposis | HHT features: epistaxis in younger years, pulmonary AVM | ||
| O'Malley et al. (2019) [81] | Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | 13 | JPS-HHT syndrome, FHx of JPS | Ovarian mass with moderate ascites – > R) ovarian immature teratoma |
| Karnsakul et al. (2018) [61] | Exon 8; MH2 domain | Substitution; missense | c.1052A > T | p.(Asp351Val) | Uncertain significance | 6 | > 100 colonic juvenile polyps removed via colonoscopy and polypectomy | Juvenile idiopathic arthritis: presented with fever, poor weight gain, upper and lower limb joint swelling & erythema. Features of HHT: digital clubbing, pulmonary and hepatic AVMs |
| Bruceta et al. (2018) [16] | Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 44 | > 100 gastric juvenile polyps, few colorectal polyps | Nil features of HHT; other: embolic strokes from atrial septal aneurysm and patent foramen ovale |
| Bishop et al. (2018) [9] | Exon 8; MH2 domain | Substitution; missense | c.1052A > T | p.(Asp351Val) | Uncertain significance | 6 | > 50 colonic juvenile polyps with diagnosis of JPS-HHT syndrome | Systemic juvenile idiopathic arthritis: knee/ankle pain with swelling; Hx of being premature, Henoch-Schonlein purpura; HHT features: clubbing, pulmonary and hepatic AVM, aortic dilation |
| Wiener et al. (2017) [107] | Exon 10; MH2 domain | Substitution; nonsense | c.1333C > T | p.(Arg445*) | Pathogenic (unconfirmed) | N/A | Nil JPS, FHx of JPS (colonic polyps) | Aortic root dilation with surgical replacement, R) common iliac artery aneurysm; HHT features: epistaxis, telangiectasia |
| Ramos et al. (2016) [87] | Exon 11; MH2 domain | Substitution; missense | c.1561A > C | p.(Thr521Pro) | Uncertain significance | N/A | Duodenal sessile/pendunculated juvenile polyps throughout, tubular adenoma with low grade dysplasia, severe anaemia; FHx of gastric cancer | Hx of ulcerative colitis with total colectomy and ileostony, HHT features: FHx of HHT, epistaxis, telangiectasia, large angioectasia throughout the stomach (angiodysplasia) |
| Kadiyska et al. (2016) [57] | Exon 11; MH2 domain | Deletion; frameshift | c.? | p.(Arg531Glyfs*6) | Pathogenic (unconfirmed) | 11 | One hyperplastic colonic polyp (11y) w/ rectal bleeds, no GI symptoms since | Features of HHT: FHx of HHT, epistaxis, telangiectasia, pulmonary AVM; Other: embolic stroke (30y) |
| Exon 11; MH2 domain | Deletion; frameshift | c.? | p.(Arg531Glyfs*6) | Pathogenic (unconfirmed) | 6 | N/A | Features of HHT: clubbing, cyanosis, pulmonary AVM, FHx of HHT (maternal) | |
| Burmester et al. (2016) [18] | Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | Family with 3 cases of JPS (colorectal polyps), 1 case of JPS-Menetrier's disease | 5 cases of Menetrier's disease, 7 cases of asthma, 8 cases of epistaxis, 5 cases of GORD, 4 cases of gastritis, 14 cases of migraine headaches | |
| Brosens et al. (2016) [15] | Not described | Not described | Not described | p.? | #N/A | 30 | ~ 27 colorectal juvenile/inflammatory polyps and multiple gastric hyperplastic polyps | Neurofibromatosis-1 diagnosed at 2y with café-au-lait spots, axillary freckling, bilateral optic nerve gliomas and cutaneous neurofibromas, and FHx of NF-1 |
| Soer et al. (2015) [98] | Not described | Deletion of SMAD4 gene | Not described | p.? | #N/A | 40 | Multiple gastric, small bowel and colonic adenomatous polyps (15) with low grade dysplasia, had gastrectomy, metastatic GI cancer; FHx of son with duodenal & rectal polyps | |
| Deletion of exons 1–8 | c.(?_-127–1)_(1139 + 1_1140-1)del | p.? | #N/A | 48 | Multiple gastric polyps, two colonic inflammatory polyps, with iron deficiency anaemia | |||
| Ngeow et al. (2015) [78] | SMAD9; MH1 domain | Substitution; missense | #N/A | #N/A | #N/A | 38 | ~ 30 diffuse colonic polyposis (hamartomatous with adipose or ganglioneuroma proliferation) with family history of paternal diffuse polyposis, CRC with deaths in 40s | |
| Lin et al. (2015) [70] | Exon 10; MH2 domain | Substitution | c.1342C > T | p.(Gln448*) | Pathogenic | 14 | 15 pedunculated/sessile colonic juvenile polyps, integrated into bowel wall | HHT features: epistaxis, telangiectasia, FHx of pulmonary AVMs |
| Oliveira et al. (2014) [79] | Balanced translocation | c.(?_-538)_(*6575_?)del | p.0 | Pathogenic (unconfirmed) | 10 | JPS with multiple colonic juvenile polyps with annual colonoscopies, with tubular adenomas by 11y, and multiple adenomatous colonic polyposis by 13y | Other: facial dysmorphism, intellectual disability, developmental delay, ADHD, corpus callosum agenesis HHT features: epistaxis, brain AVM, telangiectasia (JPS-HHT) | |
| Teekakirikul et al. (2013) [103] | Exon 10; MH2 domain | Duplication; frameshift | c.1349_1376dup | p.(Ala460Glyfs*43) | Likely pathogenic | 7 | Multiple juvenile polyps throughout GI tract with low-grade dysplasia with total abdominal colectomy (11y) | Aortopathy: mild dilation of aortic annulus and aortic root; HHT features: pulmonary AVMs, epistaxis |
| Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 6 | Colonic juvenile polyps, with partial colectomy and multiple polypectomies | Aortopathy: mild aortic root dilation, family history of sudden cardiac death (acute aortic dissection of father); HHT features: pulmonary and hepatic AVM, epistaxis, FHx of HHT; Other: Marfan syndrome, PFO, myclonic epilepsy, TIA, migraine, sleep apnoea, spondylolisthesis | |
| Honda et al. (2013) [44] | Exon 11; MH2 domain | Substitution; nonsense | c.1421C > G | p.(Ser474*) | Pathogenic (unconfirmed) | 29 | Familial JPS with numerous gastric (predominant) + colonic juvenile polyps, necessitating gastrectomy, family history of gastric polyps and CRC | |
| Exon 11; MH2 domain | Substitution; nonsense | c.1421C > G | p.(Ser474*) | Pathogenic (unconfirmed) | 57 | Familial and generalised JPS with multiple gastric (predominant) + small bowel + colonic juvenile polyps, with history of polypectomies | ||
| Jee et al. (2013) [52] | Exon 10; MH2 domain | Substitution; nonsense | c.1239C > G | p.(Tyr413*) | Pathogenic | 21 | Multiple juvenile polyps in stomach, small bowel & colon, with family history of mother with gastric polyposis & CRC (gastrectomy, right hemicolectomy) | |
| Stadler et al. (2012) [99] | Exon 11; MH2 domain | Insertion | c.1507_1508insATCC | p.(Met503Asnfs*25) | Pathogenic (unconfirmed) | 38 | Diffuse, severe grape-like gastric hyperplastic polyps, and many large colonic polyps, with total gastrectomy + right hemicolectomy with family history of early onset gastric cancer (death of sister/father in 40s) | |
| Schwetz et al. (2012) [95] | Exon 4; Linker domain | Deletion | c.543del | p.(Ile182Serfs*20) | Pathogenic (unconfirmed) | 8 | Ileocolic intussusception with massive colonic polyposis w/ total colectomy | Family history: grandmother (52y massive polyposis of stomach with total gastrectomy), 7/9 family members with gastric manifestations, 2/9 gallbladder polyps, 3/9 GI AVMs ?JP-HHT |
| Piepoli et al. (2012) [82] | Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 4 | Familial JPS with several colonic polyps with tubular adenoma & gastric hyperplastic polyps (with H.pylori infection) | |
| Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 13 | Familial JPS with numerous colonic juveile polyps with tubular adenoma & gastric polyps (with H.pylori infection) | ||
| Exon 9; MH2 domain | Deletion; frameshift | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 17 | Familial JPS with innumerable gastric polyps (with H.pylori infection), few rectal hyperplastic polyps | Menetrier's gastropathy | |
| Zimmer et al. (2011) [110] | Exon 9; MH2 domain | Substitution; missense | c.1157G > A | p.(Gly386Asp) | Pathogenic/Likely pathogenic | 10 | Diffuse colorectal juvenile polyposis, several gastric polyps, large duodenal juvenile polyps | HHT: Ileal AVM, digital clubbing, pulmonary AVM |
| Andrabi et al. (2011) [2] | Exon 10; MH2 domain | Substitution; nonsense | c.1333C > T | p.(Arg445*) | Pathogenic | 7 | Some colonic hamartomatous polyps | Mild mitral regurgitation, family history of sudden cardiac death, Marfan's syndrome; HHT: epistaxis |
| Not tested | Not tested | Not tested | 21 | 5–10 colonic juvenile polyps | Mild aortic dilatation, severe mitral regurgitation, mitral valve prolapse with "Marfan-like CTD" (passed away at 21—arrhythmia precipitated by mitral valve prolapse with underlying marfanoid features) | |||
| Exon 10; MH2 domain | Substitution; nonsense | c.1333C > T | p.(Arg445*) | Pathogenic | 27 | Colonic polyps | Normal echocardiogram in adulthood | |
| Exon 10; MH2 domain | Substitution; nonsense | c.1333C > T | p.(Arg445*) | Pathogenic | 5 | Mulitple juvenile colonic polyps with total colectomy (19y) | Mild aortic dilatation, mitral valve prolapse | |
| Not tested | Not tested | Not tested | 43 | Multiple colonic juvenile and some adenomatous polyps with metastatic colorectal cancer (pulmonary metastases) | Aortic dilatation, severe mitral regurgitation (passed away at 43) | |||
| Poletto et al. (2010) [85] | Not tested | Not tested | Not tested | 9 | Multiple juvenile polyps throughout the colon with family history of JPS (mother) | HHT: epistaxis, digital clubbing, pulmonary AVM, left-to-right shunt, family history of HHT (epistaxis, haemoptysis, telangiectasia, pulmonary AVM) | ||
| Iyer et al. (2010) [51] | Exon 9; MH2 domain | Deletion | c.1228_1229del | p.(Gln410Glufs*18) | Pathogenic | 24 | JPS diagnosed given multiple harmatomatous polyps throughout the colon, with total colectomy | HHT: epistaxis, telangiectasia, pulmonary AVM, brain AVM—HHT |
| Pitiliciuc et al. (2008) [83] | Exon 11; MH2 domain | Substitution; nonsense | c.1527G > A | p.(Trp509*) | Pathogenic | 31 | Generalised juvenile polyposis: Gastric polyps of hypertrophic and polypoid nature with foveolar hyperplasia, nil colorectal/SB polyps, with family history of CRC and gastric cancer | |
| Exon 9; MH2 domain | Deletion | c.1245_1248del | p.(Asp415Glufs*20) | Pathogenic | 38 | Generalised juvenile polyposis: Multiple colonic hyperplastic polyps w/ hypertrophic and polypoid gastropathy, on the background of villous caecal tumour & right hemicolectomy | Menetrier's disease; Hx of R) ovarian teratoma, uterine fibroma, autoimmune hyperthyroidism, lobular breast carcinoma, FHx of brain and breast cancer | |
| Shikata et al. (2005) [97] | Exon 5; Linker domain | Insertion; frameshift | c.692dup | p.(Ser232Glnfs*3) | Pathogenic | 24 | GJP: Profuse gastric polyposis with small areas of adenocarcinoma, nil intestinal polyps, treated with gastrectomy | HHT: pulmonary AVM; other: paroxysmal VT with cardio defibrillator |
| Lamireau et al. (2005) [64] | Exon 11; MH2 domain | Substitution; nonsense | c.1236C > G | p.(Tyr412*) | Pathogenic | 5 | Several colonic juvenile polyps with adenomatous component, large ileal juvenile polyp caussing intussesception | Hypertrophic osteoarthropathy: digital clubbing of finger and toes (acro-osteolysis of distal phalanges of toes with soft-tissue swelling) |
| Exon 11; MH2 domain | Substitution; nonsense | c.1236C > G | p.(Tyr412*) | Pathogenic | 3 | Several colonic juvenile polyps | Hypertrophic osteoarthropathy: digital clubbing of finger and toes (acro-osteolysis of distal phalanges of toes with soft-tissue swelling) | |
| Burger et al. (2002) [17] | Exon 9; MH2 domain | Substitution; missense | c.1157G > A | p.Gly386Asp | Pathogenic/Likely pathogenic | 11 | 70 colonic juvenile polyps | HHT: pulmonary AVM, digital clubbing |
| Baert et al. (1983) [7] | #N/A | #N/A | #N/A | 15 | Juvenile intestinal polyposis involving duodenum and colon | Hypertrophic osteoarthropathy: finger clubbing, pretibial swelling – > extensive bilateral laminated new bone formation of ulna and right radius, hands and feet; HHT: pulmonary AVM | ||