Thoracic aortic aneurysm or dissection (GMS)

Gene: COL1A1

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 4 Dec 2024, 9:45 p.m. | Last Modified: 4 Dec 2024, 9:45 p.m.

Panel Version: 3.19

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Comment on list classification: This gene was reassessed in light of the Green review by Neeti Ghali (NWTRGS). The evidence suggests that vascular complications can be observed in a subset of cases. Colman et al. 2022 (PMID: 35587586) reviewed previously reported cases and showed that 10/35 individuals presented with vascular phenotypes (4 artery dissection, 3 aneurysms (1 requiring embolisation), 2 aortic root dilation, 1 ascending aorta dilation, 3 arterial tortuosity).

In cases where vascular abnormalities are present, this panel may serve as an important diagnostic pathway, as highlighted by Neeti Ghali.

Upgrading from Red to Amber; however, due to conflicting expert reviews, this gene will be flagged for further GMS specialist assessment during the next iteration of GMS panel updates to determine if it should be made Green.

Created: 6 Jun 2024, 4:40 p.m. | Last Modified: 7 Jun 2024, 9:16 a.m.

Panel Version: 3.14

Green List (high evidence)

Several non-glycine substitutions have been linked to phenotypes overlapping with vascular EDS. Specific arginine to cysteine substitutions. Small numbers but Colmans et al. 2022 summarise the literature well: 10/35 have vascular complications/abnormalities (including 7 artery dissections/aneurysms) and recommend ongoing cardiovascular surveillance (echo and MRA head to pelvis). Regarding classification, they propose the Arg to Cys variants are classified as a separate entity given the risk of severe vascular complications. It is most definitely a separate entity to OI. They highlight the importance of gene panel testing given the clinical overlap between the EDS types. A family has been identified through 100K genome project. I can see below that other reviewers have suggested this should not be on the R125 panel because it is an EDS gene. But COL5A1/COL5A2/COL3A1/PLOD1 are (quite appropriately) also on the R125 therefore this argument is not a strong reason for it to not be included.

Created: 6 Jun 2024, 3:05 p.m. | Last Modified: 6 Jun 2024, 3:05 p.m.

Panel Version: 3.11

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
skin (soft, doughy, hyperextensible, fragile) with atrophic scarring; musculoskeletal (joint hypermobility, dislocations, spinal and chest wall deformities); vascular complications (see below)

Publications

• 35587586

Mode of pathogenicity
Other

Red List (low evidence)

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Red on this panel.

Created: 18 Nov 2019, 4:33 p.m. | Last Modified: 18 Nov 2019, 4:33 p.m.

Panel Version: 0.35

Red List (low evidence)

Associated with OI, little association with aortopathy.

Created: 2 Oct 2019, 3:09 p.m. | Last Modified: 2 Oct 2019, 3:09 p.m.

Panel Version: 0.32

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Caffey disease 114000; Ehlers-Danlos syndrome, arthrochalasia type, 1 130060; Osteogenesis imperfecta, types I-IV

Publications

• 14630726

I don't know

Present on Wessex aortopathy panel, pathogenic variants have been detected in patients referred with OI, but no pathogenic or likely pathogenic variants have been detected in patients referred specifically for aortopathy (without other COL1A1 specific syndromic features e.g. OI). Associated with EDS (arthrochalasia type) OMIM #130060 and OI (OMIM #166200,166210, 259420, 166220).

Created: 29 Aug 2019, 2:18 p.m. | Last Modified: 29 Aug 2019, 2:19 p.m.

Panel Version: 0.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

130060 AD Ehler's Danlos syndrome arthrochalasia type 1, which does not have a cardiac/aortopathy phenotype associated on OMIM; gene also causative of osteogeneisis imperfecta. Should this be included as it is similar situation to some of the red genes - involved in CTD but without aortopathy.

Created: 25 Mar 2019, 4:30 p.m.

Weerakkody et al 2016 Genet Med 18:1119 PMID:27011056 is one of several publications identifying variants in COL1A1 in EDS patients. One frameshift and two missense (affecting glycine in the G-X-Y collagen triple-helix motif) variants are described: c.1265delG: p.Gly422AlafsX119; c.643G>A: p.Gly215Ser; c.662G>C: p.Gly221Ala. None of these have any gnomAD frequency.

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

PMID:26188975 perform WES in 102 TAAD patients using a 21-gene panel including COL1A1, COL1A2 and COL5A2: 2 patients had suspicious variants of unknown significance in COL1A1- V349F (previously reported in association with OI) and N1394S.

Created: 29 Jun 2017, 11:30 a.m.

COL1A1 is on this panel for syndromic TAAD: patients with syndromic thoracic aortic aneurysm suffer from conditions including Ehlers-Danlos syndrome (EDS). Osteogenesis Imperfecta (OI) patients can also present with TAAD as a secondary feature (PMID:10523481).

Created: 29 Jun 2017, 11:30 a.m.

Comment when marking as ready: Definite disease-causing gene, with phenotype overlapping Thoracic Aortic Aneurysm Disease

Created: 19 Feb 2016, 2:39 p.m.

Green List (high evidence)

Mice with a deletion in the first intron of the Col1a1 gene develop age-dependent aortic dissection and rupture (PMID: 14630726). Lower incidence of TAAD in humans harbouring COL1A1 mutations (PMID: 14630726)

Created: 12 Feb 2016, 11 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
#130000- Ehlers-Danlos syndrome, classic; #130060- Ehlers-Danlos syndrome, type VIIA

Publications

• PMID: 14630726
• 26188975

I don't know

Comment on list classification: Demoted from Amber to Red, after confirmation with the GMS Cardiology specialist disease group in a meeting in July 2019 that EDS genes should not be included, except vascular EDS (the COL3A1 should remain Green).

Created: 30 Aug 2019, 10:09 a.m. | Last Modified: 30 Aug 2019, 10:09 a.m.

Panel Version: 0.9

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Not on the Inherited Cardiac Condition Genes panel for Familial aortic anuerysm reported in: Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Pua et al, Journal of Cardiovascular Translational Research, online Feb 2016 (doi:10.​1007/​s12265-016-9673-5). The panel contains disease-causing, putatively pathogenic, research and phenocopy genes.

Created: 19 Feb 2016, 10:54 a.m.

Comment on phenotypes: Sourced from OMIM

Created: 1 Feb 2016, 11:29 a.m.