A new publication entitled A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8 has just been published in The American Journal of Human Genetics (AJHG) and is co-authored by two members of our Heritable Thoracic Aortic Diseases Working Group (HTAD WG), Professor Bart Loeys and Dr. Aline Verstraeten.
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Researchers from the Cardiogenomics research group at the Centre for Medical Genetics (University of Antwerp/UZA) have been investigating the mechanisms underlying thoracic aortic dilatation (TAA), which refers to a pathological and progressive dilatation of the aorta that, left untreated, can lead to a risk of a life-threatening aortic dissection or rupture. While most often inherited in an autosomal dominant manner, rare X-linked or autosomal recessive families have also been reported. Pathogenic variants in the more than 30 known TAA-associated genes are thought to explain less than 30% of probands with a positive family history, so additional TAA-associated genes are yet to be identified.
In this latest publication, researchers identified a new genetic cause for a syndromic form of TAA with clinical overlap with Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, structural heart defects, motor developmental delay, connective tissue findings (e.g. hypermobile joints) and craniofacial dysmorphic features. All were found to have loss-of-function variants in the importin-8 gene (IPO8) gene, which encodes the importin-8 protein.
As the importin-8 protein is a key molecule involved in a process previously linked to syndromic TAA, it represents a candidate drug target for TAA and future studies may lead to new treatment discoveries.
Reference: Van Gucht I, Meester JAN, Bento JR, Bastiaansen M, Bastianen J, Luyckx I, Van Den Heuvel L, Neutel CHG, Guns PJ, Vermont M, Fransen E, Perik MHAM, Velchev JD, Alaerts M, Schepers D, Peeters S, Pintelon I, Almesned A, Ferla MP, Taylor JC, Dallosso AR, Williams M, Evans J; Genomics England Research Consortium, Rosenfeld JA, Sluysmans T, Rodrigues D, Chikermane A, Bharmappanavara G, Vijayakumar K, Mottaghi Moghaddam Shahri H, Hashemi N, Torbati PN, Toosi MB, Al-Hassnan ZN, Vogt J, Revencu N, Maystadt I, Miller EM, Weaver KN, Begtrup A, Houlden H, Murphy D, Maroofian R, Pagnamenta AT, Van Laer L, Loeys BL, Verstraeten A. A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. Am J Hum Genet. 2021 Jun 3;108(6):1115-1125. doi: 10.1016/j.ajhg.2021.04.019. Epub 2021 May 18. PMID: 34010605.
