Osteogenesis imperfecta

Osteogenesis imperfecta (OI) may be caused by changes (mutations) in any of several genes.

OI is most commonly due to a variation (mutation) in either the collagen genes COL1A1 or COL1A2 gene, which cause OI types I through IV.  The collagen genes play a role in how the body makes collagen, a material that helps to strengthen the bones. The type and severity of OI depends on the effect that the specific variation has on normal collagen production.^[3] OI caused by mutations in these genes is inherited in an autosomal dominant manner. Most of the variations that cause OI type I occur in the COL1A1 gene.

In about 10% of people with OI, the COL1A1 and COL1A2 genes are normal and the condition is due to variations in other genes; many of these people have an autosomal recessive form of OI.^[3][4] Variation in the CRTAP gene usually cause OI type VII; and variations in the  LEPRE1 gene (also called P3H1 gene) are classified as type VIII. 

Types V and VI do not have a type 1 collagen variation, but the genes causing them have not yet been identified. However, there are other genes in which variations may be responsible for these types or other less common types of OI, which have been reported in only one individual or family:

IFITM5 (type V)
SERPINF1 (type VI)
PPIB (type IX)
SERPINH1 (type X)
FKBP10 (type XI)
SP7 (type XII)
BMP1 (type XIII)
TMEM38B (type XIV)
WNT1 (type XV)
SPARC (type XVII)

Osteogenesis imperfecta (OI) types I, II, III, IV, V and VI, are inherited in an autosomal dominant manner.^[5][1] This means that having only one changed (mutated) copy of the responsible gene in each cell is enough to cause features of OI. The mutated copy of the gene may be inherited from an affected parent, or it may occur for the first time in an affected person (a de novo mutation). When a person with an autosomal dominant form of OI has children, each child has a 50% (1 in 2) chance of inheriting the mutated gene.^[6] If the child inherits the mutated gene, the child's symptoms may be milder, or more severe, than those of the parent.^[7]

OI subtypes  VII and VIII (and some cases of type III) are inherited in an autosomal recessive manner.^[5] This means that both copies of the responsible gene in each cell must have a mutation for a person to be affected. The parents of a person with an autosomal recessive condition typically are unaffected, but each carry one mutated copy of the gene. When two carriers of an autosomal recessive form of OI have children, each child has a 25% (1 in 4) chance to be affected, a 50% (1 in 2) chance to be a carrier like each parent, and a 25% chance to be unaffected and not be a carrier.^[7]

People concerned about inheritance risks for OI should talk with a genetic professional.

Genetic testing is available for individuals with osteogenesis imperfecta. The rate for detecting mutations in the genes that are responsible for OI varies depending on the type.^[8] Carrier testing may be available to relatives of affected individuals if the type of OI, disease-causing gene, and specific mutation in the affected individual are known.

Prenatal testing for at-risk pregnancies can be performed by analysis of collagen made by fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation if an abnormality of collagen has been identified in cells from the affected individual. Analysis of collagen after an amniocentesis (usually performed at 15-20 weeks gestation) is not useful, because the cells obtained do not produce type I collagen. However, prenatal testing can be performed by analyzing the genes (molecular genetic testing) if the specific mutation has been identified in the affected relative.^[8]

GeneTests lists the names of laboratories that are performing genetic testing for different types of osteogenesis imperfecta. To view the contact information for the clinical laboratories conducting testing, click here and click on "Testing" next to the type of OI in which you are interested. Please note that most of the laboratories listed through GeneTests do not accept direct contact from patients and their families; therefore, if you are interested in learning more, you will need to work with a health care provider or genetics professional. Genetics professionals, such as genetic counselors, can also explain the inheritance of OI in detail including information about genetic risks to specific family members.