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PGD with HLA Matching
Preimplantation Genetic Diagnosis (PGD) of single gene disorders, combined with HLA matching,
represents one of the most recent applications in reproductive medicine. This strategy has emerged
as a tool for couples at risk of transmitting a genetic disease to select unaffected embryos of a
Human Leukocyte Antigen (HLA) tissue type compatible with that of an existing affected child. At
delivering, stem cells from the newborn umbilical cord blood can be used to treat the affected sibling.
Allogeneic haematopoietic stem cell (HSC) transplantation represents the only curative option for severe
cases of haematopoietic disorders, including ß-thalassemia that has been recently classified as a public
health problem. The best possibilities of cure are provided by transplantation with HLA-identical donors,
because transplantation using donors other than HLA-identical siblings is associated with high morbidity
and poor survival. Unfortunately, this cannot be applied in the majority of cases because of the difficulty
to find HLA-matched donors, even among family members.
Umbilical cord blood from HLA-identical siblings has been reported as an excellent source of stem cells.
Therefore, an increasing number of couples with a child affected by such a disease are requesting preimplantation
HLA matching to conceive a healthy child who would became a future donor of HSC, to provide radical treatment
for the existing affected recipient sibling.
PGD with HLA Matching Technique:
RGI has developed a new strategy optimized for PGD of hemoglobinopathies combined with HLA matching.
This procedure involves a minisequencing-based genotyping of HLA regions A, B, C, and DRB combined with
mutation analysis of the gene regions involved by mutation. Analysis of at least 8 polymorphic STR markers
scattered through the HLA complex has also been included to detect potential contamination and crossing-over
occurrences between HLA genes. The above assay can also be used for preimplantation HLA matching as a primary
indication. This approach permits HLA genotyping in preimplantation embryos combined with analysis of single
gene disorders, by use of a flexible protocol that can be applied to a wide spectrum of different HLA allele
combinations, reducing notably time needed for preclinical set-up of each PGD case.
Should the parents be anyway thinking of having another baby, IVF can be used to expose more of the eggs a
woman produces each month to her husband’s sperm. If the eggs are fertilized in an IVF lab, the combination
of HLA genes the different fertilized eggs contain can be determined by special testing within a few days.
By analyzing embryos produced from an IVF cycle, we can identify embryos that are a match to a sibling
requiring a marrow transplant. This can be done in conjunction with a specific disease test, such as hyper IgM.
We generate a mini DNA fingerprint of the affected child’s HLA region and determine if the HLA region in an
embryo is the same as the affected infant. As well, we can determine beforehand if the likelihood of a match
s compromised by genetic recombination (the normal process by which genes are “shuffled” on transmission from
one generation to the next).
Ethically the salient points are that every month a woman tries to conceive she will produce many potentially
fertilizable eggs, one of which randomly ends up exposed to sperm. For her and her partner, one in four
fertilizations will result in a fortuitous HLA match. If it is morally acceptable for them to produce more
fertilized eggs than normal (i.e. they accept there will be early embryos that will be discarded), then in
principle RGI is prepared to help.
A suitable embryo is transferred to the uterus and, following delivery, fetal stem cells are harvested
from the umbilical cord blood and prepared for transfusion into the sick child after his or her own bone
marrow cells have been destroyed as part of the chemotherapy treatment.
PGD with HLA Matching Treatment Value:
The above technique outlines preimplantation HLA matching as a part of PGD, providing a realistic option for
couples desiring to have a HLA compatible child for the treatment of affected siblings, although some limitations
must be considered. The most important is represented by the number of embryos available for screening. A good
response to hormonal hyperstimulation and a high fertilization rate are critical, as the expected probability of
having HLA-identical, unaffected embryos corresponds to 3/16 (1 embryo out of 4 is expected to be HLA-identical,
and 3 embryos out of 4 will be transferable as they are wild type or carry the mutation in the heterozygous state).
The possibility of applying this strategy to a variety of severe pathological conditions enlarges the number of
potential candidates who may benefit from programming a pregnancy with a known HLA-type. Its clinical application
may represent an alternative approach to the treatment of children with haemoglobinopathies who can benefit from
allogenic haematopoietic stem cell transplantation, including beta-thalassemia and leukaemia.
In this way we greatly increase the chance of a family being able to make use of blood that is normally
discarded at birth to save the life of another child within the family when they have in any case decided to
have another baby.
Next Steps:
Please review our PGD information packet and pamphets and contact our
genetic counselors at 773-472-4900 or e-mail
us with
any questions or inquiries
regarding our PGD program.
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Single
Gene Pamphlet
