Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria

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Type V collagen mutations are associated with classic Ehlers–Danlos Syndrome (EDS), but it is unknown for which proportion they account and to what extent other genes are involved. We analyzedCOL5A1andCOL5A2in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 wereCOL5A1mutations, 13 wereCOL5A2mutations and seven wereCOL5A1null-alleles with mutation unknown. The majority of the 73COL5A1mutations generated aCOL5A1null-allele, whereas one-third were structural mutations, scattered throughoutCOL5A1. AllCOL5A2mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring and joint hypermobility. NoCOL5A1/COL5A2mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, which indicates that this is the major—if not only—cause of classic EDS.

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