SMAD4 Gene Curation

Gene-disease assertions not curated here (add link or write note):

Disease	Juvenile polyposis / hereditary hemorrhagic telangiectasia syndrome
Inheritance	Autosomal dominant
Prevalence Possible sources Orphanet Medline Plus Genetics	1:16,000 and 1:100,000. Source: PMID: 20301642
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD	ClinGen Hemostasis Thrombosis GCEP, Accessed 07.11.2023
Clinical Validity Scoring Notes and points	The SMAD4 gene encodes for the SMAD4 protein, belonging to the SMAD family of transcription factor proteins. SMAD4 plays a pivotal role in signal transduction of the transforming growth factor beta superfamily cytokines by mediating transcriptional activation of target genes. Variants in SMAD4 are linked to 4 different phenotypes: juvenile polyposis with hereditary hemorrhagic telangiectasia (HHT) syndrome, Myhre syndrome, pancreatic cancer (somatic), juvenile intestinal polyposis. We curated SMAD4 for juvenile polyposis with hereditary hemorrhagic telangiectasia syndrome. SMAD4 was first reported in relation to juvenile polyposis–HHT syndrome in 2004 (Gallione et al, PMID 15031030) in seven unrelated families or individuals displaying both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Seven different variants, 4 missense, 1 stop and 2 deletions leading to frameshift, were described in the enrolled individuals. Common phenotypes were arteriovenous malformation, juvenile polyposis and telangiectasia. Epistaxis was common as well as anemia and digital clubbing. At least 17 unique variants have been reported in humans, comprising missense, stop and frameshift variants. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (non-human model organisms). Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 24 probands in 7 publications (PMIDs: 9582123, 15235019, 15031030, 16613914, 32944796, 30210120, 22331366) leading to a score of 12 for genetic evidence. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence has been reached. The mechanism for disease is heterozygous loss of function. Summary of Experimental Data: 4 POINTS This gene-disease association is supported by evidences of non-human model organisms, indeed two SMAD4 conditional knock out murine models have been described, both recapitulate most of the juvenile polyposis–HHT phenotypes including anemia and arteriovenous malformations in the brain, gastrointestinal tract, and skin (PMID 30571376) and formation of arteriovenous malformations in the neonate retina (PMID 29460088). In summary, we found definitive association of SMAD4 with juvenile polyposis–HHT syndrome. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 12/16/2020 (SOP Version 8). The curation was updated on 2/22/2023 to include cases of classic Juveline polyposis with guidance from the Hereditary Cancer GCEP (SOP Version 9) Source: ClinGen Hemostasis Thrombosis GCEP, Accessed 07.11.2023
Clinical Validity Points Total	16 Source: ClinGen Hemostasis Thrombosis GCEP, Accessed 07.11.2023
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Definitive Source: ClinGen Hemostasis Thrombosis GCEP, Accessed 07.11.2023
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function NOTES: Many NMD+ variants. First two pulled from ClinGen curation, but since several truncations there appeared to be NMD-, pulled additional variants from HGMD. NM_005359.6(SMAD4):c.1245_1248del (p.Asp415GlufsTer20) - PMID: 30210120 case report, 52yo man dx with JP-HHT. NM_005359.6(SMAD4):c.692dup (p.Ser232GlnfsTer3) PMID: 9582123 reported in patient JP10 (table 1) NM_005359.6(SMAD4):c.302G>A (p.W101) PMID: 20101697 (table 1) Pt 4114 dx with both JP and HHT. Also has a dx of Williams syndrome. NM_005359.6(SMAD4):c.692dup p.(Ser232Glnfs3) PMID: 20101697 Pt YF1, dx of both JP and HHT. NM_005359.6(SMAD4):c.1102_1103del p.(Ser368Glnfs*9) 20101697 Pt 4269 dx with both JP and HHT
Penetrance options Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID)	Reduced, age-related Source: https://actionability.clinicalgenome.org/ac/Pediatric/ui/stg2SummaryRpt?doc=AC066
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	Congenital-adulthood Source:https://actionability.clinicalgenome.org/ac/Pediatric/ui/stg2SummaryRpt?doc=AC107 , https://actionability.clinicalgenome.org/ac/Pediatric/ui/stg2SummaryRpt?doc=AC066
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.	Moderate
Clinical Features	Predisposition to hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum. Increased risk of cancer, particularly colon cancer Gastric polyposis, gastric cancer Hereditary hemorrhagic telangiectasia, characterized by arteriovenous malformations most commonly in the brain, lung, liver. Telangiectasias are small AVMs close to the surface of the skin and mucous membranes (lips, tongue, buccal, nasal, gastrointestinal mucosa, face, fingers). Recurrent epistaxis, anemia. Pulmonary arterial hypertension Sources: https://actionability.clinicalgenome.org/ac/Pediatric/ui/stg2SummaryRpt?doc=AC107
Gene SOPs & Notes	HOMOLOGY: Please note, there is one pseudogene. Per note in `https://www.ncbi.nlm.nih.gov/books/NBK535152/` it has caused false positive results in MLPA PMID: 26165824 Technical review and potential orthogonal confirmation may be necessary. Several extension variants in HGMD, use caution when interpreting variants at the C-terminus. Tandem duplication of exon 9 reported as VUS in CLinVar (Variation ID 651595)
Curation Summary: Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited	The SMAD4 gene is associated with autosomal dominant juvenile polyposis - hereditary hemorrhagic telangiectasia syndrome
Case ID, Curator name, Date, Jira ticket link

Disease	Myhre syndrome
Inheritance	Autosomal recessive / autosomal dominant / X-linked
Prevalence Possible sources Orphanet Medline Plus Genetics	Source:
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD
Clinical Validity Scoring Notes and points	Variant/Case Evidence: Segregation Evidence: Case/Control Evidence: Experimental Evidence: Source:
Clinical Validity Points Total	Source:
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Source:
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function / Gain of function / Dominant Negative
Penetrance options Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID)	Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
Clinical Features	Sources:
Gene SOPs & Notes	LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant
Curation Summary: Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited
Case ID, Curator name, Date, Jira ticket link

SMAD4 Gene Curation

Juvenile polyposis / hereditary hemorrhagic telangiectasia syndrome

Gene SOPs & Notes

Myhre syndrome