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Aortopathy_Connective Tissue Disorders v2.1 TES Zornitza Stark Marked gene: TES as ready
Aortopathy_Connective Tissue Disorders v2.1 TES Zornitza Stark Gene: tes has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v2.1 Zornitza Stark Copied gene TES from panel Mendeliome
Aortopathy_Connective Tissue Disorders v2.1 TES Zornitza Stark gene: TES was added
gene: TES was added to Aortopathy_Connective Tissue Disorders. Sources: Expert Review Red,Literature
Mode of inheritance for gene: TES was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TES were set to 33092471
Phenotypes for gene: TES were set to Thoracic aortic aneurysm, MONDO:0005396,TES-related
Aortopathy_Connective Tissue Disorders v1.77 PMEPA1 Zornitza Stark gene: PMEPA1 was added
gene: PMEPA1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to 36928819
Phenotypes for gene: PMEPA1 were set to Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related
Mode of pathogenicity for gene: PMEPA1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PMEPA1 was set to AMBER
Added comment: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
(Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.).

Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.13 THSD4 chirag patel gene: THSD4 was added
gene: THSD4 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: THSD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THSD4 were set to PMID: 32855533
Phenotypes for gene: THSD4 were set to Thoracic aortic aneurysm and dissection (TAAD)
Review for gene: THSD4 was set to GREEN
gene: THSD4 was marked as current diagnostic
Added comment: 5 functional heterozygous variants in THSD4 (two lead to a premature termination codon) found in 5 families with TAAD. Variants segregated with disease in other family members. THSD4 encodes ADAMTSL6, a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.10 THSD4-AS1 chirag patel gene: THSD4-AS1 was added
gene: THSD4-AS1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: THSD4-AS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THSD4-AS1 were set to PMID: 32855533
Phenotypes for gene: THSD4-AS1 were set to Thoracic aortic aneurysm and dissection (TAAD)
Review for gene: THSD4-AS1 was set to GREEN
gene: THSD4-AS1 was marked as current diagnostic
Added comment: 5 functional heterozygous variants in THSD4 (two lead to a premature termination codon) found in 5 families with TAAD. Variants segregated with disease in other family members. THSD4 encodes ADAMTSL6, a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 LTBP4 Ain Roesley gene: LTBP4 was added
gene: LTBP4 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: LTBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP4 were set to PMID: 22829427
Phenotypes for gene: LTBP4 were set to Cutis laxa, autosomal recessive, type IC (MIM# 613177)
Penetrance for gene: LTBP4 were set to unknown
Review for gene: LTBP4 was set to GREEN
Added comment: PMID: 22829427;
- 9 families with cutis laxa, either homozygotes or cHets.
- all PTVs except 1 homozygous missense
- Most LTBP4 mutation positive patients (11/13) had generalized moderate to severe cutis laxa, skin was hyperextensible, or appeared translucent with a prominent venous pattern (3/9), few patients had thin and slowly growing hair and inguinal and diaphragmatic hernias (5/9)
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.134 COL12A1 Bryony Thompson gene: COL12A1 was added
gene: COL12A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: COL12A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: COL12A1 were set to 28306229; 31273343; 24334604
Phenotypes for gene: COL12A1 were set to Myopathic EDS; Bethlem myopathy 2 MIM#616471; Ullrich congenital muscular dystrophy 2 MIM#616470
Review for gene: COL12A1 was set to GREEN
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
18 cases from 12 unrelated families have been reported with monoallelic variants (both de novo and inherited), and one family has been reported with a homozygous variant. A null mouse model recapitulates the phenotype.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.96 PLOD1 Paul De Fazio gene: PLOD1 was added
gene: PLOD1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PLOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD1 were set to 28306225; 28306229
Phenotypes for gene: PLOD1 were set to Ehlers-Danlos syndrome, kyphoscoliotic type, MIM# 225400
Review for gene: PLOD1 was set to GREEN
gene: PLOD1 was marked as current diagnostic
Added comment: Review in PMID: 28306225 states: "A total of 139 mutations in PLOD1 have been identified in the 84 confirmed cases, of these there are 39 different mutations." It is included in The 2017 International Classification of the Ehlers-Danlos Syndromes (PMID: 28306229).

Medium‐sized vessel rupture has been reported in several individual case reports.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 ALDH18A1 Ain Roesley gene: ALDH18A1 was added
gene: ALDH18A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ALDH18A1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ALDH18A1 were set to PMID: 30071989; 26320891; 24913064; 18478038; 21739576; 22411858; 28228640
Phenotypes for gene: ALDH18A1 were set to Cutis laxa, autosomal dominant 3 (MIM# 616603); Cutis laxa, autosomal recessive, type IIIA (MIM# 219150)
Review for gene: ALDH18A1 was set to GREEN
Added comment: PMID: 30071989; not a HTAAD gene by clingen working group

Cutis laxa, autosomal dominant 3 (MIM# 616603)

PMID: 28228640;
- Born to consanguineous parents and harbour a de novo missense p.(Arg126His). no functional done

PMID: 26320891;
- 8 unrelated individuals born to non-consanguineous families clinically diagnosed with de-barsy syndrome (DBS) or wrinkly skin syndrome. All variants occur at codon Arg138 and parental DNA from 6 probands confirmed de novo origin. (NOTE: table 1 states paternal origin however this is referring to the allele not variant (Figure S1)).
- Imaging of patients's cells showed increased accumulation of mutant protein at the mitochondrial outer membrane.
- Biochemical studies using patients' fibroblasts demonstrated LoF


Cutis laxa, autosomal recessive, type IIIA (MIM# 219150)

PMID: 24913064;
- 2 patients from consanguineous families, 1x fs (c.2131del)+ 1x 1522bp del (resulting in exon 15 del)
- clinical features like facial dysmorphism, hypotonia, adducted thumbs and cutis laxa, which are frequently found in progeroid cutis laxa syndromes. In addition, they had cardiovascular abnormalities

PMID: 18478038;
- missense c.2350C>T; p.(His784Tyr) found in a a consanguineous New Zealand Maori family with 4 affecteds.
- patients' fibroblasts showed no defect in Proline accumulation

PMID: 21739576;
This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1 , c.1923 + 1G > A

PMID: 22411858;
pair of siblings chet for p.(Ser742Ile) and p.(Arg425Cys)
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.30 SMAD4 Paul De Fazio changed review comment from: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and so does not account for the reported individuals in PMID 30809044.

Green in PanelApp UK although with quite a few Amber reviews.

There is an association between people with with SMAD4 variants and aortic dissection (PMID 25931195).; to: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."


Green in PanelApp UK although with quite a few Amber reviews.

There is an association between people with with SMAD4 variants and aortic dissection (PMID 25931195). The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and so does not account for the reported individuals in PMID 30809044. Given this more recent data Green is appropriate.
Aortopathy_Connective Tissue Disorders v0.26 SMAD4 Paul De Fazio changed review comment from: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and does not account for the reported individuals cited below.; to: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and so does not account for the reported individuals in PMID 30809044.

Green in PanelApp UK although with quite a few Amber reviews.

There is an association between people with with SMAD4 variants and aortic dissection (PMID 25931195).
Aortopathy_Connective Tissue Disorders v0.26 SMAD4 Paul De Fazio changed review comment from: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."; to: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and does not account for the reported individuals cited below.