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*** INHERITANCE ***

O.I. is a genetic disease and, as such, is inheritable. The types I and IV sometime appear in families, through various generations. The mode of inheritance of the disease is dominant: an affected parent has a 50% chance of transmitting his/her altered gene to the offspring, and a 50% chance of transmitting the normal counterpart (we all carry two copies of any given gene, with the exception of genes linked to the sex chromosomes).

Although a certain degree of variability (e.g. the number of fractures) is observed within affected relatives, the clinical type in a given family generally remains the same through generations, since the same basic genetic defect is passed from parent to child.

OI on the other hand, is highly heterogeneous in unrelated cases: each individual case may represent a different genetic defect in the collagen genes.
OI, as other dominant genetic disorders, can appear also spontaneously. This statement is particularly true for the types III and type II (usually more severe forms of OI), but is also applicable to the other types. When a child with O.I. is born from unaffected parents, we assume that a mutation has occurred in a collagen gene. Mutations are sporadic, unpredictable events which change the DNA informational content. Most likely the mutation occurred in either gamete (ovocite or sperm cell) the merging of which gave origin to the affected baby.
In families where a spontaneous OI case occurs, the unaffected siblings do not carry the mutation so they do not have particular genetic risks for their progeny; the affected child, on the contrary, has a 50% risk of transmitting the mutant gene and therefore the disease, to his/her children, starting a new chain of hereditary OI through generations


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*** MOSAICISM ***

As for the parents, studies on a wide number of families where unaffected parents had a type II (lethal) OI baby, have shown recurrence of the disease (i.e. another pregnancy with OI) in 5-7% of the cases.
This puzzling situation at first was explained erroneously with a different mode of inheritance (autosomal recessive) and can still generate confusion (and wrong genetic advice) with clinicians who are not updated in the OI field. Peter Byers and collaborators (at the University of Seattle- USA) and, subsequently, many other investigators, have demonstrated that the recurrence of OI in families with negative clinical history is due to dominant mutations in either collagen gene (COL1A1 or COL1A2): the causal mutation, instead of involving a single germ cell, is carried only by a certain proportion of the germ cells of a given parent (either mother or father), who therefore runs the risk of generating more than one affected child.

This phenomenon is called mosaicism.
It is very difficult to recognize mosaic individuals: searching for the mutation in them would be just like to look for a needle in a haystack. Only after the mutation has been identified in the affected child (who carries it in all his/her cells), it is possible to design specific molecular assays to test the parents for the presence of mosaicism (generally detectable in both germ cells and white blood cells) and to try to estimate their hypothetical recurrence risk.
Mosaicism can occur for any clinical OI form, but so far it has been documented extensively only for the severest form (type II): its frequency has been estimated empirically to range between 5-7%.


last updated 5 August 2005