Ehlers-Danlos Syndrome classical type: A novel COL5A2 missense mutation with possible additive effect of a COL5A1 stop-gain mutation in a strongly correlated phenotype

Classical Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder (HCTD) characterized by skin hyperelasticity, joint hypermobility and general tissue fragility. Mutations in COL5A1 and COL5A2 genes, encoding the type V collagen proalpha-1 (pro-α1) and proalpha-2 (pro-α2) chains respectively, are responsible of approximately 90% cEDS patients. The molecular basis of cEDS was investigated in a 43-years-old Italian woman by Target Enrichment Approach and variants were confirmed with different method as Sanger Sequencing. The analysis revealed an already described stop-gain mutation c.3769C>T, p. (Arg1257*) (rs748870349) in exon 48 of COL5A1 gene and two additional variants located in exon 48 of COL5A2 gene, that are a novel missense mutation c.3466C>G, p. (Pro1156Ala) and a known variant c.3379C>T, p. (Arg1127Cys) (rs886055354). All mutations were in heterozygous state and located in the triple-helix domain of collagen type V. The combination/co-presence of these three different collagen mutations confirmed the phenotype of EDS patients.