Letters to the editor |
Ethics and genetics of carrier embryos
UF de Biochimie et Génétique Moléculaire, Département de Génétique et Procréation, Hôpital de la Tronche, CHU DE GRENOBLE, 38 043 Grenoble Cedex 9, France
E-mail: pray{at}chu-grenoble.fr
Sir,
In his article, G. de Wert discusses the ethic of preimplantation genetic diagnosis (PGD) for HLA typing and for carrier unaffected embryos. To my knowledge, this latter point has seldom been addressed, and I thank both the author for opening this interesting debate and Human Reproduction for letting me add my modest contribution to it.
To facilitate the discussion, I translate some of the concepts stated by the author into genetic terms: G. de Wert explains that carriers (born after PGD) have a risk of transmitting the disease to their offspring. We could translate this genotype into a trait whose phenotype would be ‘able to transmit a particular genetic disease’, although it can only be observed in the next generation if some children develop the condition. In that sense, it could be considered like a ‘very late onset disease’. Then, I agree when the author says that there are two categories of carriers: those carriers of an autosomic recessive disease who will only be burdened by the inherited mutation if later in life their reproductive partner is also carrier of a mutation on the same gene and those carrier of a recessive X-linked mutation whose sons will have one of two chances of inheriting the mutation and therefore to develop the condition. What separates the two situations is merely the likelihood of having children with the disease, that is, the likelihood of expressing the disease, in other terms, the penetrance of the condition. We are therefore considering the status of carrier like a very late onset disease with a very variable penetrance. The penetrance is very low for a carrier of an autosomic recessive disease such as cystic fibrosis: 1/100 [1/2 chance for the person to transmit the mutant allele, 1/25 that his/her partner is carrier (for a Caucasian) and 1/2 chance that he/she transmits it] and is high for carriers of X-linked recessive: 1/4, or 1/2 of the male infants.
Does the fact that we can assimilate, at least theoretically, the status of carrier with a disease make PGD acceptable? The French legislation—which must only be applied in France of course but can provide fuel for thought to everybody—states that PGD can only be carried out for severe, non-curable genetic conditions. From what we said, we cannot exclude severity: the disease will probably be severe; albeit for the affected grandchildren, it is however curable because it is more than likely that our patient’s children will have access to at least the same level of medical care that they themselves had and will in turn have the option of prenatal or preimplantation diagnosis which will ‘cure’ the disease. If we accept the postulate that carriers of today will have access to PGD, we are then no longer talking about the health of the grandchildren as stated previously but merely of the reproductive options of the carriers. Now the ‘disease’ characteristics shift from very late onset (grandchildren developing the disease) to late onset (moment of reproduction of the children), and the phenotype is no longer ‘developing the original condition’ but becomes ‘having to undergo prenatal diagnosis (PD) or PGD’. All of us know that neither of these procedures can be taken lightly, and they are both highly undesirable, but in the scale of a lifetime, the notion of ‘severity’ introduced previously can now be seriously questioned.
From this reflection, we can conclude that PGD of carriers can be assimilated to the diagnosis of a curable, mild, late onset disease with variable penetrance. Whether that penetrance is high (X-linked disease) or low (autosomic disease), such a practice is clearly prohibited by the French legislation.
To carry out PGD only for this purpose as in the given example of PGD for males, hemizygous for an X-linked disease such as haemophilia with the exclusion of all obligate carrier females seems intuitively unethical because the inconvenience would outweigh the benefit: the inconvenience is to undergo a highly invasive procedure such as PGD, and the benefit is to exclude a hypothetical risk to the offspring that can be avoided later on while doing the same procedure or perhaps even a much less burdensome one considering the likely progress in science in the next generation.
One question remains: Would it be more ethical to select unaffected embryos while in the course of realizing PGD for homozygous affected embryos? In my personal opinion, and in compliance with the French legislation, I think that the priority must be to avoid the ‘real’ disease, therefore to exclude homozygotes or hemizygotes and to maximize the chances of implantation. Among a cohort of ‘healthy’ embryos (unaffected and carriers), I believe that embryos with the highest developmental potential (best morphology) should be selected for transfer whether carriers or not. I would, however, find it acceptable to favour the transfer of non-carrier embryos given the choice among a cohort of embryos of equivalent morphology, especially because for the time being, cryopreservation of biopsied embryos is hugely unsuccessful. In that case, there is no inconvenience because PGD is already being carried out, and the benefit is to avoid the future burden and stress of PD/PGD to the individual being conceived.
Reference
de Wert G. (2005) Preimplantation genetic diagnosis: the ethics of intermediate cases. Hum Reprod 20:3261–3266.
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