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, Dong Chuan Guo, Ko Tsutsui, Marie Sylvie Gross, Ketty Kessler, Laurent Tosolini, Vincenzo Dattilo, Sebastien Dupont, Jeremie Jonquet, Maud Langeois, Louise Benarroch, Melodie Aubart, Youmna Ghaleb, Yara Abou Khalil, Mathilde Varret, Petra El KhouryBenoit Ho-Tin-Noé, Yves Alembik, Sébastien Gaertner, Bertrand Isidor, Laurent Gouya, Olivier Milleron, Kiyotoshi Sekiguchi, Dianna Milewicz, Julie De Backer, Carine Le Goff, Jean Baptiste Michel, Guillaume Jondeau, Lynn Y. Sakai, Catherine Boileau, Marianne Abifadel

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)111-122
Number of pages12
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 2021


  • THSD4
  • diagnosis
  • thoracic aortic aneurysm

ASJC Scopus subject areas

  • Genetics(clinical)


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