what-when-how
In Depth Tutorials and Information
GENETIC TESTING AND COUNSELING
IN OI
Although a diagnosis of OI can be made based on
clinical and radiologic findings, genetic testing is impor-
tant to determine the inheritance pattern. In some fami-
lies, it may be impossible to determine the inheritance
pattern just based on the pedigree. For example, a pedi-
gree with only a single affected individual could rep-
resent a recessive form, or the individual could have a
de novo
dominant mutation. A pedigree showing only
affected siblings would appear to be recessive, but the
recurrence could also be due to parental mosaicism for a
dominant mutation. Therefore, when possible, molecu-
lar testing should be performed to definitely determine
the inheritance pattern. This will allow accurate genetic
counseling in terms of recurrence risk and enable repro-
ductive options such as preimplantation genetic diagno-
sis and prenatal testing (see Chapter 26).
Genetic testing in an index case should begin with
sequencing of
COL1A1
and
COL1A2
genes, followed
by quantitative analysis to detect whole-gene and exon-
level deletions and duplications. If no alterations of
COL1A1
or
COL1A2
are found and the clinical diagnosis
is accurate, testing should proceed to include the reces-
sive genes. With this approach, it is estimated that caus-
ative mutation(s) will be found in greater than 98% of
patients with OI.
15
Although the importance of genetic testing to deter-
mine inheritance pattern and recurrence risk cannot be
overemphasized, ultimately the classification of OI (e.g.,
types I-IV) is a clinical one (see Chapter 2). There may
be some correlations between genotype and phenotype,
as discussed in the following chapter, but these are not
always generalizable and exceptions may occur. This
can be a confusing issue for families and should be clar-
ified by thorough genetic counseling. Genetic counsel-
ors can help families understand the genetic test results
in the context of the patient's clinical presentation.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
References
[19]
[20]
[21]
