Compound heterozygous mutations in COL1A1 associated with an atypical form of type I osteogenesis imperfecta

• Published in: American journal of medical genetics. Part A Vol. 173; no. 7; pp. 1907 - 1912
• Main Authors: Ackermann, Amanda M., Levine, Michael A.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2017
• Subjects: biallelic mutations; Bone mass; Bone strength; Children; collagen; Collagen (type I); Ehlers-Danlos syndrome; Fractures; Frameshift mutation; Heterozygotes; Long bone; Missense mutation; Mutation; Osteogenesis; Osteogenesis imperfecta; Procollagen; Siblings; collagen; Ehlers-Danlos syndrome; osteogenesis imperfecta; biallelic mutations
• DOI: 10.1002/ajmg.a.38238
• ISSN: 1552-4825; 1552-4833

Heterozygous mutations in the genes encoding the proα1(I) or proα2(I) chains of type I procollagen (COL1A1 and COL1A2, respectively) account for most cases of osteogenesis imperfecta (OI), a disorder characterized by reduced bone strength and increased fracture risk. COL1A1 mutations can also cause rare cases of Ehlers–Danlos syndrome (EDS), a disorder that primarily affects connective tissue and often includes reduced bone mass. Here we present a kindred of three young siblings ages 1–4 years old whose mother has a history of mild type I OI. All three children are compound heterozygotes for COL1A1 mutations, with a novel frameshift mutation (c.2522delC; p.Pro841Leufs*266) from their mother and a known missense mutation (c.3196C>T; p.R1066C) from their clinically unaffected father, which has previously been described as causing a combined type I OI/EDS phenotype. The three children exhibit features of both COL1A1 mutations: early and frequent long bone fractures, joint hyperextensibility, and blue sclerae. We describe three siblings who are the first reported surviving subjects with biallelic pathogenic COL1A1 mutations. They have a more severe form of type I OI with features of EDS that represents their compound heterozygosity for two deleterious COL1A1 mutations. Their long‐term outcomes are yet to be determined.