Ehlers Danlos syndrome with a likely monogenic cause

Gene: LOX

Green List (high evidence)

Comment on mode of inheritance: There are 2 unrelated probands reported with biallelic missense LOX variants and a shared phenotype of cutis laxa, arterial dilatation, thickened heart, bone fragility, and respiratory failure. Mouse models are supportive, with knockout mouse showing abnormal collagen fibers in skin, impaired airway development, aneurysms and aortic wall dysplasia, with death occuring shortly after birth. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 22 May 2026, 9:55 a.m. | Last Modified: 22 May 2026, 9:55 a.m.

Panel Version: 4.8

PMID: 33866545 McKenzie et al., 2021
Report of 3 babies from 2 families (Indian and Middle Eastern descent) with severe congenital cutis laxa and homozygous LOX variants: c.1021A>C, p.Thr341Pro in P1&P2, and c.749A>G, p.Tyr250Cys in P3. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity. Post-mortem examination revealed widespread ectasia and tortuosity of medium and large sized arteries, myocardial hypertrophy, rib and skull fractures. All 3 babies died before 6 months of age. Parents did not have any history of cardiac, skin, or vascular issues.

Functional models:
PMID: 16192629 Maki et al., 2005
Lox-/- knockout mice die shortly after birth, with cyanotic skin, large aortic aneurysms and aortic wall dysplasia. Impaired development of the distal and proximal airways was also noted. The amount of lysyl oxidase activity was reduced by ∼80% in cultured Lox−/− skin fibroblasts and aortic smooth muscle cells. Elastic and collagen fibers were abnormal in skin of Lox-/- mice.

PMID: 27432961 Lee et al., 2016
Mutant mice het for LOX p.Met298Arg displayed disorganized ultrastructural properties of the aortic wall characterized by fragmented elastic lamellae - consistent with milder presentation in human patients with heterozygous LOX variants.

Created: 22 May 2026, 9:54 a.m. | Last Modified: 22 May 2026, 9:54 a.m.

Panel Version: 4.8

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Aortic aneurysm, familial thoracic 10, OMIM:617168

Publications

• 16192629
• 27432961
• 33866545

Green List (high evidence)

I don't know

This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: LOX; Suggested initial gene rating: green

Created: 3 Apr 2019, 3:41 p.m.

Green List (high evidence)

Green List (high evidence)

Comment on publications: added publications evidence in more than three unrelated families

Created: 4 May 2017, 3:15 p.m.

Refer to clinical team for further discussion on wether we should include this gene on the EDS panel. There is clinical overlap between EDS and other Heritable Connective Tissue Disorders.

Created: 4 May 2017, 3:11 p.m.

Comment on phenotypes from A.Tucci: LOX can present with joint hypermobility

Created: 4 May 2017, 3:08 p.m.

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