Ehlers Danlos syndrome with a likely monogenic cause

Gene: THBS2

Agree that there is sufficient evidence for this to be an amber gene. Needs additional families to upgrade.

Created: 22 Aug 2024, 8:20 a.m. | Last Modified: 22 Aug 2024, 8:20 a.m.

Panel Version: 3.15

Comment on list classification: Upgrading from Red to Amber as this is the rating that has been supported by specialists but additional cases required before this gene can be considered as diagnostic-grade.

Created: 27 Aug 2024, 9:11 a.m. | Last Modified: 27 Aug 2024, 9:11 a.m.

Panel Version: 3.18

Comment on list classification: New gene added by Neeti Ghali (NWTRGS). Rating Red as only a single family has been reported to date (see below) but this is a good candidate for future promotion if additional cases are identified.

- PMID: 38433265 (2024) reports on a three-generation family of Ashkenazi Jewish ancestry with a previously uncharacterised connective tissue disorder with features of EDS with prominent vascular involvement, caused by a heterozygous pathogenic variant (c.2686T>C, p.Cys896Arg) in THBS2.

Created: 7 Jun 2024, 9:28 a.m. | Last Modified: 7 Jun 2024, 9:28 a.m.

Panel Version: 3.13

I don't know

For R101, I would consider this to be 'amber' (ie low-ish evidence at present). There is only one recently (March 2024) published family but mouse work was also described in this publication. The phenotype is described as a novel form of EDS with vascular features as well as musculoskeletal (joint hypermobility, tendon rupture and joint dislocations), haematological (prolonged bleeding) and dermatological features (atrophic scarring). One patient had cerebral aneurysms and died from an abdominal aorta dissection at the age of 70 (but therefore was not genetically confirmed) and one displayed an enlarged ascending aortic arch at 50 (4.2cm). Lifestyle factors were not discussed and the two younger relatives (30s) did not have aortopathy. Electron microscopy revealed abnormally disorganised collagen fibres. The variant described is a missense (Cys to Arg in highly conserved region) and a CRISPR/Cas9 knock-in mouse demonstrated phenotypic traits correlating with those observed in human subjects (but not aortopathy). Protein has been found to be mainly expressed in large blood vessels such as aorta.
Sources: Literature

Created: 6 Jun 2024, 2:30 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
vascular phenotype; joint hypermobility, tendon rupture, joint dislocations; prolonged bleeding; atrophic scarring, aortopathy

Publications

• https://doi.org/10.1038/s41431-024-01559-1

Mode of pathogenicity
Other