Journal Article Ahead of print
PubMed: 42829835 DOI: 10.1016/j.gim.2026.102741
Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features.
Genet Med
Authors: Júlia Huguet Herrero, Pauline Arnaud, Angelique Bibimbou, Deborah E Seifert, Zakaria Mougin, Louise Benarroch, Caroline Michot, Yline Capri, Lyse Ruaud, Sophie Dupuis-Girod, Alexandre Guilhem, Constance Beyler, Fanny Bajolle, Olivier Milleron, Guillaume Jondeau, Nadine Hanna, Dieter P Reinhardt, Dong-Chuan Guo, Dianna Milewicz, Catherine Boileau, Mélodie Aubart, Timothy J Mead, Carine LE Goff
Affiliations
- Université Paris Cité et Université Sorbonne Paris nord, INSERM U1148, LVTS, Paris, France.
- Université Paris Cité et Université Sorbonne Paris nord, INSERM U1148, LVTS, Paris, France; Département de Génétique, AP-HP, Bichat Hospital, Paris, France; National Reference Centre for Marfan Syndrome and related disorders, AP-HP, Bichat Hospital, Paris, France.
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
- Université Paris Cité et Université Sorbonne Paris nord, INSERM U1148, LVTS, Paris, France; University of Texas Health Science Center at Houston, Houston, TX, USA.
- Université Paris Cité et Université Sorbonne Paris nord, INSERM U1148, LVTS, Paris, France; Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en myologie, Paris, France.
- Service de Génétique, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
- Service de Génétique, AP-HP, Hôpital Robert Debré, Paris, France.
- Service de Génétique, Hospices Civils de Lyon, Bron, France.
- Service de Cardiologie, AP-HP, Hôpital Robert Debré, Paris, France.
- Service de Cardiologie, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
- Université Paris Cité et Université Sorbonne Paris nord, INSERM U1148, LVTS, Paris, France; National Reference Centre for Marfan Syndrome and related disorders, AP-HP, Bichat Hospital, Paris, France.
- Université Paris Cité et Université Sorbonne Paris nord, INSERM U1148, LVTS, Paris, France; Département de Génétique, AP-HP, Bichat Hospital, Paris, France.
- Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada; Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montréal, Canada.
- University of Texas Health Science Center at Houston, Houston, TX, USA.
- Service de Neuropédiatrie, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
- Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA; University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
- Université Paris Cité et Université Sorbonne Paris nord, INSERM U1148, LVTS, Paris, France;.
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.
MeSH
Cells, Aortic Aneurysm, Heart, Connective Tissue, Aneurysm, Fibrillins, Tissues, Loeys-Dietz Syndrome, Neurodevelopment