@article{20da7124598b486a8b0ebb8735307b4d,
title = "Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm",
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: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- 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.",
keywords = "ADAMTSL6, THSD4, diagnosis, thoracic aortic aneurysm",
author = "Sandy Elbitar and Marjolijn Renard and Pauline Arnaud and Nadine Hanna and Jacob, {Marie Paule} and Guo, {Dong Chuan} and Ko Tsutsui and Gross, {Marie Sylvie} and Ketty Kessler and Laurent Tosolini and Vincenzo Dattilo and Sebastien Dupont and Jeremie Jonquet and Maud Langeois and Louise Benarroch and Melodie Aubart and Youmna Ghaleb and {Abou Khalil}, Yara and Mathilde Varret and {El Khoury}, Petra and Benoit Ho-Tin-No{\'e} and Yves Alembik and S{\'e}bastien Gaertner and Bertrand Isidor and Laurent Gouya and Olivier Milleron and Kiyotoshi Sekiguchi and Dianna Milewicz and {De Backer}, Julie and {Le Goff}, Carine and Michel, {Jean Baptiste} and Guillaume Jondeau and Sakai, {Lynn Y.} and Catherine Boileau and Marianne Abifadel",
note = "Funding Information: We thank the patients and family members for participating in the study. We thank G. Nicolas, C. Deschildre, and A. Nicoletti (INSERM U1149 and U1148, Paris, France). This research was supported by grants from Leducq Foundation (FLQ 13CVD03), Programme Hospitalier de Recherche Clinique (AOM10108 and CRC15014), Agence Nationale de la Recherche (NONAGES, ANR-14-CE15-0012-01 and GDPM-2, ANR-10-BLAN-1129), F{\'e}d{\'e}ration Fran{\c c}aise de Cardiologie, Soci{\'e}t{\'e} Fran{\c c}aise de Cardiologie, Fondation Maladies Rares, Fondation C{\oe}ur et Recherche, Conseil de la recherche de l{\textquoteright}universit{\'e} Saint-Joseph de Beyrouth and Lebanese National Council for Scientific Research (CNRS-L), the Shriners Hospitals for Children, and the Methusalem grant from the Flemish government and Ghent University (grant number BOF15/MET-V/011). Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2021",
month = jan,
doi = "10.1038/s41436-020-00947-4",
language = "English (US)",
volume = "23",
pages = "111--122",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "1",
}