Compound phenotype of osteogenesis imperfecta and Ehlers-Danlos syndrome caused by combined mutations in COL1A1 and COL5A1

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.

Keywords: COL1A1; COL5A1; Ehlers-Danlos syndrome; Osteogenesis imperfecta; Whole exome sequencing.

Figure 1. Family pedigree

The diagonal lines indicate individuals with OI. The gray shading indicates individuals with OI and EDS. / = deceased.

Figure 2. Radiographic images, magnetic resonance imaging, and photographs of the findings in proband III-1

Radiographic images: (A) right tibia fracture, (B) right femoral fracture. (C,D) Magnetic resonance imaging (MRI) of the posterior cruciate ligament rupture in the right knee-joint. Photographs of joint hypermobility (E,F), atrophic scarring (G).

Figure 3. COL1A1 and COL5A1 variants, structure of the collagen type V α-chain, and evolutionary conservation of the COL5A1 mutated site

(A) Sequences of the genomic region mutated in COL1A1. The mutation in the mother (II-1), proband (III-1), and brother (III-2) are marked by black arrows. (B) Sequences of the mutation in COL5A1. The mutation in the mother (II-1) and proband (III-1) are marked by black arrows. (C) Structure of collagen type V α-chain: purple indicates the site of the mutation (c.5335A>G, P. N1779D) in the C-terminal propeptide. (D) The site of the COL5A1 mutation is evolutionarily conserved. The mutation is marked by a red arrow.