Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm
Sandy Elbitar, Marjolijn Renard, Pauline Arnaud, Nadine Hanna, Marie‐Paule Jacob, Dongchuan Guo, Ko Tsutsui, Marie‐Sylvie Gross, Ketty Kessler, Laurent Tosolini, Vincenzo Dattilo, Sébastien Dupont, Jérémie Jonquet, Maud Langeois, Louise Benarroch, Mélodie Aubart, Youmna Ghaleb, Yara Abou Khalil, Mathilde Varret, Petra El Khoury, Benoît Ho‐Tin‐Noé, Yves Alembik, S. Gærtner, Bertrand Isidor, Laurent Gouya, Olivier Milleron, Kiyotoshi Sekiguchi, Dianna M. Milewicz, Julie De Backer, Carine Le Goff, Jean‐Baptiste Michel, Guillaume Jondeau, Lynn Y. Sakai, Cathérine Boileau, Marianne Abifadel
Abstract
PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.