ADAMTS6 loss of function linked to a new connective tissue disorder
Exome and genome sequencing of a French cohort with syndromic or isolated hTAAD found rare damaging ADAMTS6 variants in four unrelated individuals. Functional analyses showed impaired ADAMTS6 secretion and catalytic activity, disrupting fibrillin-1 and fibrillin-2 processing. The changes led to abnormal extracellular matrix accumulation and disorganized microfibrils. Patient-derived fibroblasts and Adamts6-deficient mice showed parallel defects. Clinical presentations ranged from early-onset multisystem disease with cardiovascular, skeletal, craniofacial, and neurodevelopmental abnormalities to isolated adult-onset aortic aneurysm. The recurrent p.(Leu814Arg) variant also altered Hippo and TGFβ signaling and affected cell adhesion.
ADAMTS6 deficiency is a newly recognized connective-tissue disorder. Patients have heart defects, aortic aneurysm, and neurodevelopmental features.
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