Ariana Kariminejad - Kariminejad-Najmabadi Pathology and Genetics Center, Tehran Iran
Fransiska Malfait - Center for Medical Genetics, Ghent University Hospital, Belgium
Bita Bozorgmehr - Kariminejad-Najmabadi Pathology and Genetics Center, Tehran Iran
Tim Van Damme - Center for Medical Genetics, Ghent University Hospital, Belgium

Galactosyltransferse II (β3GALT6) encoded by B3GALT6 is a key enzyme in the synthetic pathway of proteoglycans.Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissue. By homozygosity mapping and candidate gene sequence analysis we were able to identify mutations in B3GALT6 in three independent Iranian families. The patients presented with a severe connective tissue disorder characterized by skin fragility,delayed wound healing, severe joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and aspondyloepiphyseal dysplasia with bone fragility and severe kyphoscoliosis. The phenotype was unique but had overlaps with several recessive Ehlers-Danlos variants and spondyloepiphyseal dysplasia with joint laxity. Affected individual’s fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together withimpaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming β3GalT6 loss of function.Dermal electron microscopy disclosed abnormalities in collagen fibril organization, in line with the important regulatoryrole of decorin in this process. Our study emphasizes a crucial role for β3GalT6 in multiple developmental processes and shows that mutations in B3GALT6 can cause a multi-system disorder. In this study we identified a new gene with a unique connective tissue phenotype