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Compound heterozygous mutations in COL1A1 associated with an atypical form of type I osteogenesis imperfecta
Author(s) -
Ackermann Amanda M.,
Levine Michael A.
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38238
Subject(s) - osteogenesis imperfecta , compound heterozygosity , frameshift mutation , missense mutation , dentinogenesis imperfecta , genetics , type i collagen , mutation , medicine , joint hypermobility , biology , gene , pathology , anatomy
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.