EFEMP2 has been reported in association with autosomal recessive cutis laxa type 1B (ARCL1B) in at least 49 individuals (Loeys B, De Paepe A, Urban Z GeneReviews, 2023). This gene-disease relationship was originally classified as moderate by the HTAAD GCEP in 12/22/2016. Clinical phenotypes of ARCL1B include cutis laxa, arterial tortuosity, aortic aneurysm, diaphragmatic hernia, emphysema, craniofacial features, and musculoskeletal abnormalities. Phenotype severity ranges from embryonic/perinatal lethality to asymptomatic patients with aortic aneurysm found on imaging. Seven variants (missense and frameshift) reported in 6 probands in 6 publications (PMIDs: 22440127, 30140196, 22070778, 28673110, 23532871, 20389311) are included in this curation. The mechanism of pathogenicity is proposed to be loss of function. This gene-disease association is also supported by experimental evidence including protein expression in the aorta (PMID:23715323) and protein interaction with LOX, which is also associated with aortic aneurysm (PMID:19855011). Finally, multiple KO mouse models have recapitulated phenotypes of ARCL1B including emphysema, arterial tortuosity, and aortic aneurysm (PMIDs: 16478991, 17293478). In summary, EFEMP2 is definitively associated with autosomal recessive cutis laxa type 1B and aortic aneurysm. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The evidence summary was updated by the Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease Gene Curation Expert Panel on 8/23/2024.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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