With rare exceptions, OI is considered to be a dominantly inherited disorder. In a recent survey in Finland [24], about 65 percent of individuals with OI were in families in which a prior generation was affected and the remaining 35 percent represented new mutations in a type 1 collagen gene. In general, the more severe the presentation the more likely it is that the infant represents the first affected person in the family, and is the result of a spontaneous mutation that took place near the time of conception.
The parents of a child with a de novo mutation are at no increased risk of recurrence compared to the general population. Affected individuals have a 50% risk of transmission with each pregnancy.
In some families, clinically unaffected parents will have more than one child with dominant OI. This occurs because one parent is a mosaic carrier of the mutation. Presumably, the mutation occurred during the parent’s fetal development; that parent then has both a normal and a mutant cell population. The proportion of mutant cells and their distribution in somatic and germline tissues depends on the timing of the mutation and the distribution of cells arising from the first mutant cell. [25] The frequency of occurrence of mosaic parents is relatively high in OI. Empirically, 5-10% of unaffected couples whose child has OI will be at risk of recurrence. For those couples in which one member is a mosaic carrier the recurrence risk may be as high as 50%, equivalent to the fully heterozygous state. To date, all mosaic parents have been detectable by examination of leukocyte DNA for the mutation present in their child. The mutation may also be detectable in fibroblast, hair bulb and germ cells.
For the first case of moderate to severe OI in a family, prenatal diagnosis will probably occur during ultrasound at 18 to 24 weeks’ gestation. [26] Detecting recurrence of OI prenatally is easiest if the exact collagen mutation in the affected child is known. In that case, a potential mutation in the current pregnancy can be detected early and with confidence. Cultured CVS cells can be used for DNA or RNA extraction and detection by either PCR and restriction enzyme digestion or sequencing. CVS can also be used for biochemical analysis if the known mutation causes significant collagen protein overmodification. [25] Amniocentesis is only appropriate for molecular diagnosis via RNA or DNA analysis. Biochemical analysis of amniocytes is complicated by the overproduction of α1(I) chains; the excess chains form homotrimers, which are overmodified and co-migrate with overmodified heterotrimers, potentially causing a false-positive test result. [25]
Collagen analysis is also useful when the diagnosis is equivocal. A positive collagen study can counteract charges of child abuse in mild cases, although the absence of a positive study still leaves a 5-10% chance of a false negative. A positive collagen analysis can also settle subtle distinctions between type IV OI and idiopathic juvenile osteoporosis.
From a research standpoint, each new collagen mutation delineated in OI provides information about genotype-phenotype relationships either directly or by making the cells containing that particular mutation available for studies of mechanism at the level of bone matrix. Further, mutations may vary in response to different therapeutic approaches. Determination of mutations that cause OI may allow investigators to understand which drugs or therapies will be helpful for different individuals.