Genetics in medicine : official journal of the American College of Medical Genetics · 2026
Loss of function variants in ADAMTS6: a new connective tissue disorder with heart defect, aortic aneurysm and neurodevelopmental features.
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Huguet Herrero Júlia, Arnaud Pauline, Bibimbou Angelique, Seifert Deborah E, Mougin Zakaria, Benarroch Louise, Michot Caroline, Capri Yline, Ruaud Lyse, Dupuis-Girod Sophie, Guilhem Alexandre, Beyler Constance, Bajolle Fanny, Milleron Olivier, Jondeau Guillaume, Hanna Nadine, Reinhardt Dieter P, Guo Dong-Chuan, Milewicz Dianna, Boileau Catherine, Aubart Mélodie, Mead Timothy J, LE Goff Carine
Аннотация
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.
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.