Homozygosity by descent for a COL1A2 mutation in two sibs with severe osteogenesis imperfecta and mild clinical expression in the heterozygotes

We report two sibs with severe, progressively deforming osteogenesis imperfecta (OI) and homozygosity by descent for a glycine 751 to serine substitution in the α2(I) collagen chain due to a G to A transition in the COL1A2 gene. The parents, who were first cousins, and two elder sibs were heterozygous for the mutation and presented mild clinical manifestations of OI. Collagen studies on cultured fibroblasts from one of the probands and from the father showed that cells from the homozygote produced only mutant, unstable collagen I, whereas cells from the heterozygote produced both normal and mutant collagen I. This family represents an exceptional example of autosomal recessive OI, caused by homozygosity for a missense mutation in collagen I. Received: 22 July 1996