Gene Validity Curation

TGFBR2 - familial thoracic aortic aneurysm and aortic dissection

Gene: TGFBR2 (HGNC:11773)
Classification - 02/15/2016
Disease: familial thoracic aortic aneurysm and aortic dissection (MONDO_0019625)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Evidence Summary: Assertion made by the Aortopathy working group. Considerable phenotypic variability humans and mice with different genetic background. Definitive for both LDS and nonsyndromic HTAAD.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Mátyás G et al. 2006 Aug (PMID:16791849); (1 proband with a de novo missense variant (c.1657T>A; pS553T))
Proband with predicted or proven null variant 1.5 0-2 10 0.0 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3.0 3
Pannu H et al. 2005 Jul 26 (PMID:16027248); Law C et al. 2006 Dec (PMID:16885183); Stheneur C et al. 2008 Nov (PMID:18781618); Panesi P et al. 2015 Jan (PMID:25555948); (PMID 16027248: Family TAA035, a large thoracic aortic aneurysm and aortic dissection (TAAD) kindred whose data were used to map the TAAD2 locus to 3p24–25, was found to have the TGFBR2 missense mutation 1378C to T in exon 5, resulting in the substitution of cysteine for an arginine at amino acid 460 (R460C). The same TGFBR2 mutation was present in the proband from another family . The proband presented at 41 years of age with an ascending aneurysm and mitral valve prolapse. The proband was a member of a 4-generation family with autosomal dominant inheritance of TAAD. Points 1. A second mutation was observed in two unrelated probands in two families with some evidence of co-segregation. Points=1 PMID 16885183 TGFBR2 R460H mutations in 1 large multi-generation family with TAAD and not fulfilling Marfan / LDS criteria. Point =0.5 PMID 18781618: TGFBR2 mutations in 1 TAAD(p.R537C) case and 6 “incomplete MFS” phenotypes. points=0.25 25555948: TGFBR2 mutation (5'untranslated region (c.-59C>T), predicted to be a exonic splice enhancer and shown by qRTPCR in one male with TAAD (abnormal expression in aorta). points=0.25 )
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 0.0 0
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 0.0
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 6.0 6
Hasham SN et al. 2003 Jul 1 (PMID:12821554); Pannu H et al. 2005 Jul 26 (PMID:16027248); (PMID 12821554: 4-generation family with dominant mode of inheritance of TAAD was studied. Affected status was determined by dilation of the ascending aorta, surgical repair of an aneurysm or dissection, or death as the result of aortic dissection. None of the family members evaluated met the diagnostic criteria for Marfan syndrome. After exclusion of known loci for familial TAAD, a genome-wide scan was carried out to map the defective gene causing the disease in the family. A locus was mapped to a 25-cM region on 3p24-25 with a maximum multipoint logarithm of the odds score of 4.28. Subsequently the causative locus was identified as TGFBR2 mutation (PMID 16027248). Points =5 PMID 16027248 A TGFBR2 mutation, 1379G to A, altering arginine 460 to a histidine (R460H), was identified in 2 large TAAD kindred. LOD scores were estimated from the combined family. Points =1 )
2 4
1.5 3
1 1.5
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 0.0
Aggregate Variant Analysis 0-6 12 0.0
Total Genetic Evidence Points (Maximum 12) 10
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 2.0 2
Inamoto S et al. 2010 Dec 1 (PMID:20628007); Loeys BL et al. 2005 Mar (PMID:15731757); Azhar M et al. 2003 Oct (PMID:12948523); Hu JH et al. 2015 Dec (PMID:26494233); (Biochemical Function: PMID 20628007: Induction of contractile smooth muscle cell phenotype - Inamoto et al showed reduced expression of contractile proteins & blunted response to TGFB1. Cells explanted from patients with TGFBR2 mutations + aortic tissue from these patients + transgenic mice with TGFBR2 variants showed reduced expression of VSMC contractile proteins & failed to increase expression in response to TGFB1 PMID 15731757: Increased pSMAD2 in patients with TGFBR2 mutations; Expression: PMID 12948523 : Expressed highly in vascular smooth muscle (SMC); expressed in pharyngeal arches during cardiac development. Protein Interaction: PMID 20628007 : With Col3A1 – Inamoto et al showed altered expression in patients with TGFBR2 mutations; PMID 21979435 showed altered expression in SMC-specific TGFBR2 knockouts. With TGFBR1 – Physical interaction to form heterodimer PMID 20628007: With MYH11, ACTA2 – showed that SMC-specific TGFBR2 knockouts show reduced expression of these contractile proteins. PMID 26494233: TGFBR3, Tgfb2, Tgfb3, and Smad7 – Expression of all increased after post-natal loss of TGFBR2 in mice)
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2.0 2
Inamoto S et al. 2010 Dec 1 (PMID:20628007); Mizuguchi T et al. 2004 Aug (PMID:15235604); Loeys BL et al. 2005 Mar (PMID:15731757); (Patient Cells: PMID 20628007: aortic SMCs from patients show decreased expression of SMC contractile proteins PMID 15731757:increased collagen expression, increased nuclear pSMAD2 and increased CTGF in patients with TGFBR2 mutations Non Patient Cells: PMID 15235604:transfected HEK293 cells with disease-causing variant – caused loss of TGFB stimulated extracellular matrix producation PMID 20628007: transfected mouse meseenchymal stem cells with TGFBR2 variant constructs – these failed to differentiate into an SMC phenotype with TGFB1 stimulation (control cells differentiate). )
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 4.0 4
Jaffe M et al. 2012 Jan (PMID:21979435); Li W et al. 2014 Feb (PMID:24401272); Hu JH et al. 2015 Dec (PMID:26494233); Gallo EM et al. 2014 Jan (PMID:24355923); (PMID 24401272: post-natal conditional inactivation of TGFBR2 resulting in aortopathy PMID 26494233: post-natal, SMC-specific knockout of TGFBR2 causes severe aortopathy. PMID 24355923: knock-in mice for Tgfbr2 (G357W) recapitulate aortic phenotype; PMID 21979435: smooth muscle-specific knockout of TGFBR2 in mouse model resulting in abnormal extracellular matrix deposition in aorta; Also differentiationSmooth muscle cell differentiation markers altered in expression in this mouse model. )
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 10 6 16 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Assertion made by the Aortopathy working group. Considerable phenotypic variability humans and mice with different genetic background. Definitive for both LDS and nonsyndromic HTAAD.