Thoracic aortic aneurysm or dissection (GMS)

Gene: NOTCH1

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)

Consistently associated with disorders of the outflow tract in the literature.

Created: 2 Oct 2019, 11:20 a.m. | Last Modified: 2 Oct 2019, 11:20 a.m.

Panel Version: 0.30

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

Phenotypes
Aortic valve disease 1 109730; Adams-Oliver syndrome 5 616028

Publications

• 29907982
• 18593716

Green List (high evidence)

On CGGL Royal Brompton FTAAD panel. Only VUS reported so far. Good evidence for association with aortic aneurysm in PMID: 16729972 and 26820064 (listed as limited evidence by ClinGen). Pathogenic variants also cause isolated BAV, and congenital cardiac defects via Adam-Oliver syndrome.

Created: 18 Sep 2019, 8:16 p.m. | Last Modified: 18 Sep 2019, 8:16 p.m.

Panel Version: 0.30

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

Publications

• 16729972
• 26820064

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

Green List (high evidence)

616028 Adams-Oliver syndrome - vascular abnormalities with congenital heart defects and limb abnormalities; 109730 Aortic valve disease - BAV

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

Meester et al 2018 Hum Mutat 39:1246 PMID:29924900 Characterisation of variants in Adams-Oliver syndrome missense, nonsense splice and frameshift variants either novel to this publication or also published elsewhere. Multiple variants classified pathogenic/likely pathogenic using ACMG criteria and gnomAD population data using criteria which appear to be stringent. Southgate et al 2015 Circ Cardiovasc Genet 8:572 PMID:25963545 show segregation of NOTCH1 variants in 4 families and de-novo in 3 families and reduction of mRNA levels implying NMD. Both publications list cardiac phenotypes including BAV, co-arctation of the aorta, aortic regurgitation, aortic stenosis and VSD.

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

Green List (high evidence)

PMID:16729972 report 2 sporadic BAV patients with NOTCH1 variations and ascending aortic aneurysm in both.

Created: 29 Jun 2017, 12:16 p.m.

PMID:26820064 (2016) screened NOTCH1 in 428 nonsyndromic probands with left-sided congenital heart disease- Thoracic aortic aneurysms (TAAs) and NOTCH1 mutations occurred in 6 cases.

Created: 29 Jun 2017, 12:16 p.m.

Comment on list classification: Adams Oliver syndrome, PMID: 25132448

Created: 19 Feb 2016, 3:08 p.m.

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.

On the Inherited Cardiac Condition Genes panel 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, and it is unclear from the publication whether this gene falls into the disease-causing category. One mutation is indicated in the supplemental table in this gene.

Created: 19 Feb 2016, 11 a.m.

Publications

• 23102684
• doi:10.​1007/​s12265-016-9673-5

Comment when marking as ready: 1 reviewer marked green. Promoted as ready due to significant association with familial bicuspid aortic valve disease and concomitant thoracic aortic aneurysm formation.

Created: 2 Feb 2016, 2:40 p.m.

Comment on publications: Bicuspid aortic valve (BAV) disease association with familial thoracic aortic aneurysm (TAA)- two entities considered as disease spectrum of a common developmental defect. NOTCH1 mutations found in familial calcific BAV disease with concomitant TAA.

Created: 2 Feb 2016, 2:37 p.m.