Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features.

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

Published in

Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102741. Oct 03, 2026. Epub Oct 03, 2026.

Abstract

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.
Exome and genome sequencing of a French cohort with syndromic or isolated hTAAD revealed rare damaging variants in ADAMTS6 in four unrelated individuals.
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.
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.

PMID:
42829835
Bibliographic data and abstract were imported from PubMed on 04 Oct 2026.

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