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

ADAMTS6

ADAMTS6 variants impairing its secretion and catalytic activity, disrupting processing of fibrillin-1 and fibrillin-2 with abnormal extracellular matrix accumulation and disorganized microfibrils

Marfan syndrome, Loeys-Dietz syndrome and heritable thoracic aortic aneurysms and dissections (hTAAD) remain genetically unexplained in a substantial proportion of cases. Exome and genome sequencing of a French cohort with syndromic or isolated hTAAD revealed rare damaging ADAMTS6 variants in four unrelated individuals. Functional analyses showed impaired secretion and catalytic activity, defective processing of fibrillin-1 and fibrillin-2 and disorganized microfibrils, with the recurrent p.(Leu814Arg) variant additionally altering Hippo and TGFβ signalling. Patient fibroblasts and Adamts6-deficient mice displayed parallel defects; presentations ranged from early-onset multisystem disease to isolated adult-onset aortic aneurysm.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Four unrelated cases with a solid functional body of evidence (cells, fibroblasts, mice) are enough for a serious hypothesis, not yet for an established link: replication by other teams is awaited. The spectrum, from early multisystem disease to isolated adult aneurysm, makes the real issue the interpretation of ADAMTS6 variants in exomes/genomes of undiagnosed hTAAD patients. Novel-gene status is not asserted here.

Analysis by Dr Thibaut Benquey