67 MOSAICISM IN OSTEOGENESIS IMPERFECTA

Background Osteogenesis Imperfecta (OI) is a heterogeneous group of genetic conditions characterized by bone fragility and phenotypic features such as blue sclerae, dentinogenesis imperfecta, short stature and hearing loss. Usually OI results in mutations in one of the two genes encoding type I collagen (COL1A1 and COL1A2). Clinical, radiographic, genetic, and histologic studies have delineated seven types of OI ranging from an increased fracture frequency, to a perinatal lethal form; four types result from mutations in type I collagen and account for about 90% of all instances of OI. The mode of inheritance is usually autosomal dominant; however, there is an unexpected recurrence risk of OI due to parental mosaicism for the mutation. The questions we asked were: 1) what are the minimum and measured rates of mosaicism for OI type II, 2) what is the overall risk for recurrence in mosaic families, 3) are parents mosaic for the lethal form more likely to have clinical signs of OI than those mosaic for milder forms, and 4) based on the recurrence rate can the number of cells allocated to the germ line in early embryogenesis be estimated. Study Design and Methods We found all infants with OI type II in the Collagen Diagnostic Laboratory and identified recurrent families by family structure. When possible, we identified the mosaic parent by family structure or by direct analysis of the underlying mutation and examined clinical records. Results The minimum recurrence rate in mosaic families with OI type II was 32% (9 of 28) and the measured rate is about 12.5%. We identified 30 families out of 746 (4%) in which there were at least two affected infants born to apparently unaffected parents. In 32 families with a parent mosaic for OI type II, one parent had mild to moderate clinical signs in 9 families (28%), in 20 no information was available and in 3 both parents were normal (9%). In 10 families with a mosaic parent for OI type III/IV, one parent had mild clinical signs in 1 family (10%), in 3 no information was available and in 6 both parents were normal (60%). Conclusions: The minimum rate of parental mosaicism in OI type II is 4% and the measured rate 12.5%. The rate of recurrence in families mosaic for OI type II mutations is 32%. In a significant number of families, the mosaic parent has some signs of OI, which is more likely in the severe form of OI. The rate of recurrence in mosaic families (32%) is consistent with a small number of cells (2-4) being allocated to the germ line early in embryogenesis.