Molecular genetics in <i>classic</i> Ehlers–Danlos syndrome

AbstractClassic Ehlers–Danlos syndrome is a heritable disorder of connective tissue that is characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. Mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2‐chain of type V collagen respectively, are identified in approximately 50% of patients with a clinical diagnosis of classic EDS. In approximately one third of patients, the disease is caused by a mutation leading to a non‐functional COL5A1 allele, and resulting in haplo‐insufficiency of type V collagen. In a smaller proportion of patients, a structural mutation in COL5A1 or COL5A2, resulting in the production of a functionally defective type V collagen protein, is responsible for the phenotype. Inter‐ and intrafamilial phenotypic variability is observed, but no genotype–phenotype correlations can be made so far. The relatively low mutation detection rate in the COL5A1/A2 genes suggests genetic heterogeneity. Indeed rarely mutations in type I collagen have been identified in patients with classic EDS. Mutations in the gene for tenascin‐X have been impl