{
  "abstract": "PURPOSE: Marfan syndrome, Loeys-Dietz syndrome, and heritable thoracic aortic aneurysms and dissections (hTAAD) are autosomal dominant connective-tissue disorders with overlapping features and considerable genetic variability. Many cases arise from pathogenic variants affecting extracellular matrix (ECM) components or TGFβ signaling, yet a substantial proportion of hTAAD cases remain genetically unexplained. This study aimed to identify new genetic contributors to aortic disease and to clarify their molecular and clinical impact. METHODS: Exome and genome sequencing of a French cohort with syndromic or isolated hTAAD revealed rare damaging variants in ADAMTS6 in four unrelated individuals. RESULTS: Functional analyses showed that these variants impaired ADAMTS6 secretion and catalytic activity, disrupting the processing of fibrillin-1 and fibrillin-2, leading to abnormal ECM accumulation and disorganized microfibrils. The recurrent p.(Leu814Arg) variant additionally altered Hippo and TGFβ signaling and affected cell adhesion. Patient-derived fibroblasts and Adamts6-deficient mice exhibited parallel pathological defects, supporting ADAMTS6 loss-of-function as disease-causing Clinically, presentations ranged from early-onset multisystem disease with cardiovascular, skeletal, craniofacial, and neurodevelopmental abnormalities to isolated adult-onset aortic aneurysm. CONCLUSION: these findings establish ADAMTS6 deficiency as a newly recognized connective-tissue disorder with heart defects, aortic aneurysm, and neurodevelopmental features, highlighting ADAMTS6's key role in ECM integrity.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 23,
  "authors": [
    {
      "name": "Júlia Huguet Herrero"
    },
    {
      "name": "Pauline Arnaud"
    },
    {
      "name": "Angelique Bibimbou"
    },
    {
      "name": "Deborah Seifert"
    },
    {
      "name": "Zakaria Mougin"
    },
    {
      "name": "Louise Benarroch"
    },
    {
      "name": "Caroline Michot"
    },
    {
      "name": "Yline Capri"
    },
    {
      "name": "Lyse Ruaud"
    },
    {
      "name": "Sophie Dupuis-Girod"
    },
    {
      "name": "Alexandre Guilhem"
    },
    {
      "name": "Constance Beyler"
    },
    {
      "name": "Fanny Bajolle"
    },
    {
      "name": "Olivier Milleron"
    },
    {
      "name": "Guillaume Jondeau"
    },
    {
      "name": "Nadine Hanna"
    },
    {
      "name": "Dieter Reinhardt"
    },
    {
      "name": "Dong-Chuan Guo"
    },
    {
      "name": "Dianna Milewicz"
    },
    {
      "name": "Catherine Boileau"
    },
    {
      "name": "Mélodie Aubart"
    },
    {
      "name": "Timothy Mead"
    },
    {
      "name": "Carine Le Goff"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2fnhxmvmd8k64.bib",
  "cited_by": 0,
  "doi": "10.1016/j.gim.2026.102741",
  "fulltext_url": null,
  "id": "2fnhxmvmd8k64",
  "issns": [
    "1098-3600",
    "1530-0366"
  ],
  "landing_url": "https://hal.science/hal-05794938v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "openalex",
      "1311|Connective tissue disorders research"
    ]
  ],
  "openalex": "W7218693156",
  "pdf_url": "https://www.gimjournal.org/article/S1098-3600(26)01059-2/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-12",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/2fnhxmvmd8k64.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:54Z",
      "native_id": "hal-05794938",
      "source": "hal",
      "url": "https://hal.science/hal-05794938v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Connective tissue disorders research",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features",
  "title_text": "Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:54Z",
  "url": "https://research.draconitic.com/paper/2fnhxmvmd8k64",
  "venue": "Genetics in Medicine",
  "versions": []
}