GLY802ASP SUBSTITUTION IN THE PROA2(I) COLLAGEN CHAIN IN A FAMILY WITH RECURRENT OSTEOGENESIS IMPERFECTA DUE TO PATERNAL MOSAICISM

A proband with osteogenesis imperfecta (OI) type III/IV was born to cl inically normal parents, who subsequently had two pregnancies terminat ed because of OI in the fetuses. Cultured fibroblasts from the proband , one fetus and the father produced abnormal collagen I. Cyanogen brom ide mapping localised the defect to the region of the alpha 1(I)CB7 pe ptide. Sequencing revealed a G to A transition at nucleotide 2814 in C OL1A2 in the proband, the fetus, and the father, which resulted in a G ly802Asp substitution in the pro alpha 2(I) collagen chain. About 25% of the paternal alleles from fibroblasts and leucocytes and 40% of pat ernal alleles from spermatocytes carried the mutation consistent with somatic and germinal mosaicism. For genetic counselling, parental mosa icism must be considered in all sporadic cases of OI.