 My name is Francesca Malfe and my name is Delfin Six. We work at the Center for Medical Genetics in Ghent, Belgium. With this video highlight, we would like to present a recent manuscript entitled Genetic Hitrogenity and Clinical Variability in Muscular Contractural Illers-Danlos Syndrome caused by impaired intermittent sulfate biosynthesis, which has been published in Human Mutation. The Illers-Danlos Syndrome, or shortly EDS, comprises a heterogeneous group of connective tissue disorders that are clinically home-worked by a combination of skin hyperexensibility, joint hypermobility and generalized connective tissue fragility. The latest EDS classification, known as the Ville-Françoisology, recognises six subtypes which are mainly caused by defects in fibroids or procollagens or collagen-modifying enzymes. Over the years, several additional rare EDS and EDS-like variants have been clinically delineated and diverse molecular causes have been identified. One of the emerging causes of EDS are defects in proteoglycan biosynthesis. Proteoglycans consist of a core protein, conveniently attached to a glycosaminoglycan chain via a tetrasecarite-linked region. The alternating addition of galnuc and glucuronic acid commits the nascent glycosaminoglycan chain to chondroitin, and subsequent sulfation of the galnuc residues results in the formation of chondroitin sulfate. Alternatively, the glucuronic acid residues can be epimerized to idironic acid by two dermatone sulfate epimerases, followed by galnuc sulfation in order to form dermatone sulfate. Both dermatone sulfate epimerases and dermatone sulfo-transferase are crucial for proper dermatone sulfate biosynthesis. One of these enzymes, dermatone 4-0-sulfo-transferase-1, is encoded by the CHST-14 gene. Recently, we identified BLLX-CHST-14 mutations in a subset of patients with an EDS-6B phenotype which we coined muscular-contractual EDS. The effects in CHST-14 were already reported into other recessive conditions, adduct-temp-globfoot syndrome, and EDS-cosho-type. Based on the overlapping phenotypic characteristics, these three conditions were concluded to be a single, clinical-recognizable form of EDS, referred to as T4-ST1-deficient EDS. In our paper, we studied seven individuals originating from five families with a muscular-contractual EDS phenotype. In four of these families, we identified novel homozygous mutations in the CHST-14 gene. Comprehensive analysis of the clinical hallmarks of OR-31-reported patients revealed that they generally present with typical chronic ufacial abnormalities that are recognizable at birth. Coutaneous features, including soft and hyper-extensible skin with atrophic scars, easy bruising and palmarinckling, and musculoskeletal features, most notably typical congenital joint contractures of hands and feet. These features occur often in combination with one or more other clinical manifestations which can affect several organ systems as summarized here. Recently, locus heterogeneity was proposed for muscular-contractual EDS based on the identification of a single patient with mutations in the DSE gene and coding dermatone sulfate epimerase 1. Since we could not identify CHST-14 mutations in family 5, we screened the DSE gene and identified the second miscellaneous mutation located adjacent to the previously reported mutation. Clerical evaluation of all patients showed that DSE defects are associated with a somewhat milder phenotype compared to CHST-14 defects. Without severe complications of the urogenital, gastrointestinal, respiratory, ocular and central nervous systems. Nevertheless, due to a limited number of patients with DSE mutations, it is currently impossible to make clear clinical distinctions between defects in these two genes. Studies by us and others have indicated that mutations in CHST-14 and DSE alter the composition of the dermatone sulfate chains to a different extent. In the absence of functional dermatone sulfo-transferase, sulfation of galnach is prevented, thereby allowing back epimerization of the adjacent euronic acid residues. Subsequent sulfation by conroutine sulfo-transferases results in excessive conroutine sulfate formation and near-complete absence of dermatone sulfate. In case of dermatone sulfate epimerase 1 deficiency, reduced epimerization also leads to an increased formation of conroutine sulfate. However, a limited number of glucuronic acid residues are epimerized to euronic acid. This allows sulfation of galnach by dermatone sulfo-transferase and, as such, still a minor fraction of dermatone sulfate is present. In summary, mutations in both CHST-14 and DSE affect proper dermatone sulfate biosynthesis. The decreased to absent amounts of dermatone sulfate have an impact on the interactions between dermatone sulfate proteoglycans and other constituents of the excess cellar matrix. This is illustrated by the disturbed deposition and organization of several excess cellar matrix components, including fibronectin and types I, III and V collagen. In addition, disturbances in the dermal collagen fibril ultrastructure can be observed in patients with CHST-14 mutations. In patients with DSE mutations, no pronounced ultrastructural alterations were seen. This could be attributed to the residual presence of dermatone sulfate moieties, which can also contribute to the apparent mylar phenotype in these patients. Combined with the disturbed balance between chondroitin sulfate and dermatone sulfate during cell differentiation and development, these alterations give rise to the multisystemic muscular-contractural EDS phenotype. We would like to thank ORCO authors for the fruitful collaboration and all patients who participated in the study. For more information and clinical details, refer you to our manuscript and hope you enjoy reading it. Thank you for watching our video and feel free to contact us if you have further questions.