HOMOZYGOSITY BY DESCENT FOR A COL1A2 MUTATION IN 2 SIBS WITH SEVERE OSTEOGENESIS IMPERFECTA AND MILD CLINICAL EXPRESSION IN THE HETEROZYGOTES

We report two sibs with severe, progressively deforming osteogenesis i mperfecta (OI) and homozygosity by descent for a glycine 751 to serine substitution in the alpha 2(I) collagen chain due to a G to A transit ion in the COL1A2 gene. The parents, who were first cousins, and two e lder sibs were heterozygous for the mutation and presented mild clinic al manifestations of OI. Collagen studies on cultured fibroblasts from one of the probands and from the father showed that cells from the ho mozygote produced only mutant, unstable collagen I, whereas cells from the heterozygote produced both normal and mutant collagen I. This fam ily represents an exceptional example of autosomal recessive OI, cause d by homozygosity for a missense mutation in collagen I.