Thoracic aortic aneurysm or dissection (GMS)

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, 9:53 a.m. | Last Modified: 22 May 2026, 9:53 a.m.

Panel Version: 5.1

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, 9:49 a.m. | Last Modified: 22 May 2026, 9:49 a.m.

Panel Version: 5.1

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)

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel. Therefore this gene has been promoted from Amber to Green

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

Panel Version: 0.35

Green List (high evidence)

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

Phenotypes
Aortic aneurysm, familial thoracic 10 617168

Publications

• 26838787
• 27432961

Green List (high evidence)

On CGGL Royal Brompton FTAAD panel. Likely pathogenic variants detected where dilated aortic root and h/o pneumothorax were presenting features.
Missense and truncating variants described in the literature segregating with disease in several families, and reported by other diagnostic laboratories (eg: OMIM ref 153455; Lee et al (2016) Proc Natl Acad Sci 113(31):8759-8764; Guo et al (2016) Circ Res 118(6):928-34; ClinVar IDs 489315, 424133). ExAC LOF pLi score for LOX is 0.98, suggesting that LOF is not tolerated

Created: 18 Sep 2019, 7:47 p.m. | Last Modified: 18 Sep 2019, 7:47 p.m.

Panel Version: 0.30

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

Phenotypes
OMIM: 617168 Aortic aneurysm, familial thoracic 10

Publications

• 26838787
• 27432961

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

Green List (high evidence)

617168 Familial thoracic aortic aneursym

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

Guo et al 2016 Circ Res 118:928 PMID:26838787 LOX c.839G>T (p.Ser280Arg) segregates with FTAAD in a large family and other variants also show segregation in other families c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). Some (but not all) patients had additional Marfaniod features.

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

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

I don't know

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.

Comment when marking as ready: Marked LOX as ready: July 4th 2017.

Created: 4 Jul 2017, 2:59 p.m.

Comment on list classification: Updated rating from grey to green. Green review from gene submitter (Bill Newman) and >3 unrelated cases supporting causation. Plus on the ClinGen 'Familial thoracic aortic aneurysm and aortic dissection' (TAAD) panel with Strong evidence (https://search.clinicalgenome.org/kb/gene-validity)

Created: 4 Jul 2017, 2:59 p.m.

Comment on mode of inheritance: Monoallelic mode of inheritance confirmed by OMIM and literature.

Created: 26 Jun 2017, 12:35 p.m.

>3 unrelated cases supporting causation from two 2016 papers: PMID:26838787: WES in one family with thoracic aortic aneurysm and aortic dissection (TAAD) identified a rare coding variant in LOX. Exome and/or Sanger sequencing of LOX from 410 additional probands found 8 rare coding variants. PMID:27432961: WES in two first cousins with TAAD identified a rare missense mutation (M298R) in LOX that co-segregated with disease.

Created: 26 Jun 2017, 12:35 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
aortic aneurysm

Publications

• Circ Res. 2016 Mar 18
• 118(6):928-34. doi: 10.1161/CIRCRESAHA.115.307130. PMID: 26838787
• Proc Natl Acad Sci U S A. 2016 Aug 2
• 113(31):8759-64. doi: 10.1073/pnas.1601442113. PMID: 27432961