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 analyzed COL5A1 and COL5A2 in 126 patients with a 
diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect 
was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations and seven 
were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 
mutations generated a COL5A1 null-allele, whereas one-third were structural 
mutations, scattered throughout COL5A1. All COL5A2 mutations 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. No 
COL5A1/COL5A2 mutation 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.