Tissue specific mosaicism for a lethal COL1A1 mutation causes mild Ehlers-Danlos syndrome

Type I collagen is the predominant protein of multiple connective tissues such as skin and bone. Mutations leading to structural abnormal type I collagen mainly cause the brittle bone disease Osteogenesis imperfecta (OI), resulting in a wide spectrum of clinical severity ranging from few fractures to intra-uterine lethality with multiple fractures and malformations of the (long) bones.Until now, 1417 unique mutations in the type I collagen genes (COL1A1 and COL1A2) have been reported, of which in-frame deletions account for only 3% and all are almost exclusively associated with a severe-to-lethal OI phenotype.We describe a patient who was referred because of clinical symptoms of Ehlers-Danlos syndrome, including fragile skin, recurrent luxations and easy bruising. Biochemical collagen analysis of the patientsU+2019 dermal fibroblasts surprisingly showed dedoubling of the type I collagen bands, a finding specific for structural defects in type I collagen. Subsequent molecular analysis by Sanger sequencing detected an in-frame deletion in exon 44 of the COL1A1 gene (c.3150_3158del), resulting in the deletion of three amino acids (p.(Ala1053_Gly1055del)) in the triple helical collagen domain. This COL1A1 mutation has hitherto only been identified in four probands with lethal OI. However, the peaks on the electropherogram corresponding to the mutant allele were decreased in intensity, suggesting the mosaic presence of the COL1A1 mutation. We applied next generation sequencing in order to determine the possibility of mosaicism in skin and blood. While approximately 9% of the reads originating from DNA extracted from fibroblasts harboured the COL1A1 deletion, the deletion was not detected in DNA extracted from blood, implying that the degree of mosaicism is different between tissues thereby explaining the mild phenotype of the patient.In conclusion, the biochemical and molecular characterization of the patient described in this study illustrates that the combined use of biochemical collagen analysis and next generation sequencing technologies is a powerful tool in guiding molecular analysis and in pinpointing the clinical diagnosis in those patients in whom the diagnosis is unclear.

Publication year:2015