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Loss of function variants in ADAMTS6 : Connective tissue, Heart defect, thoracic Aortic aneurysm and Neuro

Júlia Huguet Herrero, Pauline Arnaud, Angelique Bibimbou

Medrxiv : the Preprint Server for Health Sciences

|July 14, 2025

Insights

Researchers identified rare variants in the ADAMTS6 gene, revealing a new connective tissue disorder called CHANS. This discovery expands understanding of vascular diseases and extracellular matrix regulation.

Area of Science:

Genetics and Molecular Biology
Cardiovascular Research
Rare Diseases

Background:

Marfan syndrome, Loeys-Dietz syndrome, and hTAAD are connective tissue disorders with overlapping features.
Pathogenic variants in ECM or TGFβ signaling genes explain most cases, but many hTAAD cases remain idiopathic.
ADAMTS6's role in extracellular matrix homeostasis is not fully understood.

Purpose of the Study:

To investigate the genetic basis of idiopathic hTAAD and syndromic connective tissue disorders.
To identify novel genes associated with these conditions.
To elucidate the function of ADAMTS6 in connective tissue integrity and vascular health.

Main Methods:

Exome and genome sequencing in a French diagnostic cohort.
Functional studies including protein secretion assays and extracellular matrix processing analysis.
In vitro studies using patient-derived fibroblasts and in vivo studies using Adamts6-deficient mice.

Main Results:

Rare deleterious variants in ADAMTS6 were identified in four unrelated individuals with vascular disease.
These variants impair ADAMTS6 secretion and function, affecting fibrillin-1 and fibrillin-2 processing.
ADAMTS6 deficiency leads to ECM accumulation, microfibril disorganization, and disruption of Hippo and TGFβ signaling.
A novel connective tissue disorder, CHANS (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental Syndrome), is proposed, linked to ADAMTS6 loss-of-function.

Conclusions:

ADAMTS6 deficiency defines a new connective tissue disorder, CHANS.
This finding expands the spectrum of ADAMTS-related pathologies.
ADAMTS6 plays a critical role in vascular and extracellular matrix homeostasis.

Read full analysis

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.

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