Arterial Tortuosity Syndrome: clinical and molecular findings in 12 newly identified families. B. Callewaert, A. Willaert, J. De Backer, B. Loeys, P.J. Coucke, A. De Paepe Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

   Background: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity and aneurysms of the large and middle-sized arteries. Recently, mutations in SLC2A10 were identified in this condition. This gene encodes the facilitative glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. Methods: Twelve newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. Results and conclusions: All 16 patients harbor bi-allelic SLC2A10 mutations and haplotype analysis suggests founder effects for all 5 recurrent mutations. Facial resemblance was obvious and all patients had involvement of the skin and skeleton. Remarkably, patients were significantly older than those previously reported in literature (p=0.04) and only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, 7 patients had localized arterial stenoses and 5 had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. HbA1c levels and glucose tolerance tests were normal in 6 patients and 8 heterozygous individuals of 5 families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS.