Abstract
Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with a broad clinical spectrum that can overlap with Ehlers–Danlos syndrome (EDS). To date, patients with both OI and EDS have rarely been reported. In the present study, we investigated a family with four members, one healthy individual, one displaying OI only, and two displaying the compound phenotype of OI and EDS, and identified the pathogenic mutations. Whole exome sequencing was applied to the proband and her brother. To verify that the mutations were responsible for the pathogenesis, conventional Sanger sequencing was performed for all members of the family. We identified a known COL1A1 (encoding collagen type I α 1 chain) mutation (c.2010delT, p.Gly671Alafs*95) in all three patients (the proband, her brother, and her mother) in this family, but also a novel heterozygous COL5A1 (encoding collagen type V α 1 chain) mutation (c.5335A>G, p.N1779D) in the region encoding the C-terminal propeptide domain in the proband and her mother, who both had the compound phenotype of OI and EDS. The results of the present study suggested that the proband and her mother presented with the compound OI–EDS phenotype caused by pathogenic mutations in COL5A1 and COL1A1.
Highlights
Osteogenesis imperfecta (OI), or brittle bone disease, is a clinically and genetically heterogeneous disorder that mainly results in osteopenia, bone fragility, blue sclerae, dentinogenesis imperfecta, and hearing loss [1]
We report a rare family presenting with a compound phenotype of OI and Ehlers–Danlos syndrome (EDS), such as multiple fractures, blue sclerae, atrophic scarring, easy bruising, and joint hypermobility
Thereafter, fractures of long bones occurred three times, and her knee ligament ruptured when she was involved in a car accident at 17 years old
Summary
Osteogenesis imperfecta (OI), or brittle bone disease, is a clinically and genetically heterogeneous disorder that mainly results in osteopenia, bone fragility, blue sclerae, dentinogenesis imperfecta, and hearing loss [1]. The OI Mutation Consortium, an international collaboration of many laboratories that identify OI mutations, has found that 80% of COL1A1/COL1A2 mutations give rise to substitution of glycine residues in the type I collagen chain, and the remaining 20% of mutations result in abnormalities of mRNA splicing [3]. Mutations in the gene coding type I procollagen produce a range of disorders, including autosomal dominant OI and the rare arthrochalasis subtype of Ehlers–Danlos syndrome (EDS) [4–6]. EDS is a connective tissue disorder that is characterized by abnormal wound healing, easy bruising, atrophic scarring, and joint hypermobility [7]. Classic-type EDS (cEDS) occurs because of a COL5A1/2 (encoding collagen type V α 1 or 2 chain) mutation and is inherited in an autosomal dominant manner. It is estimated that approximately 50% of patients with cEDS harbor a COL5A1 or COL5A2 mutation [7]
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