What causes OI?

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Osteogenesis imperfecta (OI) is the result of a mutation in one of the two genes that carry instructions for making type 1 collagen (the major protein in bone and skin). Collagen is the major protein of the body’s connective tissue and can be likened to the framework around which a building is constructed. In OI, a person has either less collagen than normal, or a poorer quality of collagen than normal, leading to weak bones that fracture easily. There are essentially three scenarios that occur to cause a child to be born with osteogenesis imperfecta. 1. Direct Genetic Inheritance from a Parent Most cases of OI involve a dominant gene mutation. When a gene with a dominant mutation is paired with a normal gene, the faulty gene “dominates” the normal gene. When a mutation is dominant, a person only has to receive one faulty gene to have a genetic disorder. This is the case with most people who have OI: they have one faulty gene for type 1 collagen, and one normal gene for type 1 collagen. If this person conceives a child, he or she will pass on one of the two genes to their child. Therefore, there is a 50 percent chance that his or her child will inherit the faulty gene. If the child inherits the faulty gene, he or she will have the same type of OI as the parent. However, the child may be affected in different ways than the parent (e.g., the child’s number of fractures, level of mobility, stature, etc. may not be identical to his or her parent’s). If the parent with OI passes on his or her normal gene to a child, that child will not have OI and cannot pass on the disorder to his or her own children. 2. A New Dominant Genetic Mutation In about 25 percent of cases, children with OI are born into a family with no history of the disorder, the genetic defect occurs as a “new” or “spontaneous” dominant mutation. The gene spontaneously mutated in either the sperm or the egg before the child’s conception. Now that the child has a dominant gene for OI, he or she has a 50 percent chance of passing the disorder on to his or her children, as explained above. As far as we know, nothing the parents did caused a spontaneous mutation to occur. There are no known environmental, dietary, or behavioral triggers for this type of mutation. In most cases, when a family with no history of OI has a child with OI, they are not at any greater risk than the general population for having a second child with OI. (For the exception to this rule, see “Mosaicism” below.) In addition, unaffected siblings of a person with OI are at no greater risk of having children with OI than the general population. Because the defect—whether inherited or due to a spontaneous mutation—is usually dominant, a person with OI has a 50 percent chance of passing on the disorder to each of his or her children. 3. Mosaicism In studies of families into which infants with OI Type II (the peri-natal lethal form) were born, it was found that most of the babies had a new dominant mutation in a collagen gene. However, in some of these families, more than one infant was born with OI. Previously, researchers had seen this recurrence as evidence of recessive inheritance of this form of OI. More recently, however, researchers have concluded that the rare recurrence of OI in a previously unaffected family is more likely due to a phenomenon called mosaicism. Most researchers now agree that recessive inheritance rarely causes osteogenesis imperfecta.   Genetic counselors can help people with OI and their family members further understand OI genetics and the possibility of recurrence, and assist in prenatal diagnosis for those who wish to exercise that option. References Fast Facts on Osteogenesis Imperfecta OI Issues: Genetics - OI Foundation Factsheet