Thoracic aortic aneurysm or dissection (GMS)

Gene: EFEMP2

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)

Table 1 of Brownstein et al 2017 Aorta. Associated with aortic aneurysm.

Created: 2 Oct 2019, 11:02 a.m. | Last Modified: 2 Oct 2019, 11:02 a.m.

Panel Version: 0.30

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cutis laxa, autosomal recessive, type IB 614437

Publications

• 28868310
• 22440127

Green List (high evidence)

On CGGL Royal Brompton FTAAD panel. Good evidence for syndromic aortic aneurysm

Created: 18 Sep 2019, 9:01 p.m. | Last Modified: 18 Sep 2019, 9:01 p.m.

Panel Version: 0.30

Publications

• 20019329
• 17937443
• 22440127

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

Green List (high evidence)

614437 Cutis Laxa - CTD phenotype including aortic/pulmonory artery anuerysms and arterial/venous tortuosity, arterial stenosis and vascular fragility. Missense, splicing and frameshift variants

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

Letard et al 2018 Mol Syndromol 9:190 PMID:30140196 report a severe cutis laxa phenotype in a terminated pregnancy homozygous for an EFEMP2 nonsense variant c.639C>A (p.Cys213*) and review/list previously reported EFEMP2 variants. 0.00041% gnomAD (AR association).

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

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Green List (high evidence)

PMID:22440127 (2012) recruited 9 patients, from 4 unrelated consanguineous families, with recessively-inherited aortic aneurysm. ECG revealed a wide spectrum of severity of AA but skin manifestations of cutis laxa were not found in any patient. Sequence analysis of EFEMP2 identified a novel homozygous variend (p.E161K) in all 9 affected patients. This reference forms the basis for the ClinGen TAAD 'moderate' evidence assignment.

Created: 11 Oct 2017, 11:39 a.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
#614437- Cutis laxa, autosomal recessive, type IB

Publications

• PMID: 20019329
• 17937443

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 listed in this gene in supplemental table.

Created: 19 Feb 2016, 10:22 a.m.

PMID: 16685658 is a case report of a female with severe, recessive connective-tissue disease including cutis laxa, bone fragility, vascular tortuosity and aneurysm, developmental emphysema, and diaphragmatic and inguinal hernia. At age 2 years, she received a diagnosis of an aortic root aneurysm. Screening of FBLN4 revealed a homozygous missense mutation (169G>A; E57K) in the patient. Both parents were heterozygous.

Created: 1 Feb 2016, 11:58 a.m.

PMID: 17937443 is a case report of a female with compound heterozygous mutations c.835C > T (p.R279C)/c.1070_1073dupCCGC in fibulin 4 (EFEMP2), who died at 27 days of age. Autopsy examination of the patient showed apparently long hands, bronchopneumonia with focal alveolar damage, arterial wall thickening, acute renal tubular damage, biventricular hypertrophy and right ventricle dilatation, aneurysmal dilation of the ascending aorta and main branches of pulmonary arteries with dissection of the wall. There was intussusception-like telescoping of the inner arterial layer causing severe luminal narrowing of the main branches of the pulmonary arteries. The pregnancy was complicated by maternal cocaine abuse and tobacco smoking.

Created: 1 Feb 2016, 11:50 a.m.

Previously known as FBLN4.

Created: 1 Feb 2016, 11:34 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
PMID: 17937443; 16685658; 22440127