Abstract
Marfan syndrome (MS), Loeys-Dietz syndrome (LDS), and heritable thoracic aortic aneurysms and dissections (hTAAD) are autosomal dominant connective tissue disorders with overlapping clinical features and underlying molecular heterogeneity. While most cases are explained by pathogenic variants in genes involved in extracellular matrix structure or TGFβ signaling, a large proportion of hTAAD cases remain idiopathic. Through exome and genome sequencing in a French diagnostic cohort, we identified rare deleterious variants in ADAMTS6 in four unrelated individuals with syndromic or isolated vascular disease. Functional studies demonstrated that these variants impair ADAMTS6 secretion or function, particularly in processing fibrillin-1 (FBN1) and fibrillin-2 (FBN2), resulting in extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signaling pathways and altered cell adhesion. Analysis of a patient-derived fibroblast model and Adamts6 -deficient mice supported a pathogenic role for ADAMTS6 loss-of-function in a novel connective tissue disorder. Clinical phenotypes spanned from early-onset syndromic presentations with cardiovascular, craniofacial, skeletal, and neurodevelopmental involvement to isolated adult-onset hTAAD. We propose ADAMTS6 deficiency defines a new connective tissue disorder, termed CHANS (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental Syndrome), expanding the spectrum of ADAMTS-related pathologies and highlighting its key role in vascular and ECM homeostasis.