Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features
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.
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BibTeX
@article{herrero2026loss,
title = {{Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features}},
author = {Júlia Huguet Herrero and Pauline Arnaud and Angelique Bibimbou and Deborah Seifert and Zakaria Mougin and Louise Benarroch and Caroline Michot and Yline Capri and Lyse Ruaud and Sophie Dupuis-Girod and Alexandre Guilhem and Constance Beyler and Fanny Bajolle and Olivier Milleron and Guillaume Jondeau and Nadine Hanna and Dieter Reinhardt and Dong-Chuan Guo and Dianna Milewicz and Catherine Boileau and Mélodie Aubart and Timothy Mead and Carine Le Goff},
journal = {Genetics in Medicine},
year = {2026},
month = oct,
doi = {10.1016/j.gim.2026.102741},
url = {https://hal.science/hal-05794938v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features
AU - Júlia Huguet Herrero
AU - Pauline Arnaud
AU - Angelique Bibimbou
AU - Deborah Seifert
AU - Zakaria Mougin
AU - Louise Benarroch
AU - Caroline Michot
AU - Yline Capri
AU - Lyse Ruaud
AU - Sophie Dupuis-Girod
AU - Alexandre Guilhem
AU - Constance Beyler
AU - Fanny Bajolle
AU - Olivier Milleron
AU - Guillaume Jondeau
AU - Nadine Hanna
AU - Dieter Reinhardt
AU - Dong-Chuan Guo
AU - Dianna Milewicz
AU - Catherine Boileau
AU - Mélodie Aubart
AU - Timothy Mead
AU - Carine Le Goff
PY - 2026
DA - 2026/10/12
JO - Genetics in Medicine
DO - 10.1016/j.gim.2026.102741
UR - https://hal.science/hal-05794938v1
AB - 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.
SN - 1098-3600
SN - 1530-0366
ER -