Thoracic aortic aneurysm or dissection (GMS)

Gene: PMEPA1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 4 Dec 2024, 9:45 p.m. | Last Modified: 4 Dec 2024, 9:45 p.m.

Panel Version: 3.19

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Comment on list classification: New gene submitted by Andrew Mumford (University of Bristol). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 36928819 describes 8 families with truncating variants affecting the same polycytosine area in this gene. In the 100KGP cohort, three families of European ancestry with FTAAD have the same variant. This same variant was identified independently in 3 families of Japanese ancestry in a separate Japanese patient group. A second variant in the same polycycstine stretch was identified in a different FTAAD case enrolled in the 100KGP pilot programme. A third variant (5 bp deletion in the same stretch which caused a frameshift mutation) was identified in a family in Belgium.

"All pedigrees exhibited dominant inheritance of aortic aneurysm disease with incomplete penetrance and skeletal features including pectus deformity, scoliosis and arachnodactyly with complete penetrance". The authors found four HPO terms related to the musculoskeletal system were significantly enriched, which suggested the phenotypic characteristics of the syndromic aortopathy Loeys–Dietz syndrome.

Based on the above evidence this gene has been given an Amber gene rating and should be promoted to Green at the next GMS review.

Created: 6 Nov 2023, 11:40 a.m. | Last Modified: 6 Nov 2023, 11:40 a.m.

Panel Version: 3.6

Green List (high evidence)

Association between chain truncation variants in cytoplasmic domain of PMEPA1 and 'Loeys-Dietz' phenotype was established in an association analysis in 100KGP RD main programme, but reproduced in multiple independent pedigrees reported in PMID:36928819. Gene encodes regulator of TGFBeta signalling, a pathway implicated in other familial thoracic aneurysm disorders.
Sources: Research

Created: 6 Sep 2023, 9:07 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
thoracic aortic aneurysm; tall stature; dolichocephaly; abnormal axial skeletal morphology; pes planus

Publications

• PMID:36928819