The following article was published in Clinical Genetics, February, 1996.
Preimplantation Genetic Testing for Huntington Disease and Certain Other Domintantly Inherited Disorders
JOSEPH D. SCHULMAN (1,3), SUSAN H. BLACK (1,3) ALAN HANDYSIDE (2) AND WALTER E. NANCE (3)
Genetics & IVF Institute, Fairfax, Virginia (1), Human Embryology Group, Institute of Obstetrics and Gynecology, Hammersmith Hospital, London (2), and Department of Human Genetics, Medical College of Virginia, Richmond, Virginia (3).
Keywords: antenatal diagnosis, dominant traits, Huntington disease, in vitro fertilization (IVF), Preimplantation Genetic Diagnosis (PGD), genetic disease prevention
Genetic testing for serious dominantly inherited traits for which there is no effective treatment is an excellent example of the difficult and sometimes unexpected dilemmas that the application of genetic technology can raise. In this situation, the natural desire of patients to avoid the transmission of a genetic disease to their children may conflict with and be completely extinguished by the adverse effects of presymptomatic diagnosis in the at-risk parent. In the case of Huntington disease, this dilemma has led to the development of elaborate protocols to ensure that at-risk individuals understand and are emotionally competent to accept all of the implications of presymptomatic diagnosis. In practice, only a minority of adults who are at risk elect to have presymptomatic testing (Quaid & Morris, 1993; Craufurd et al., 1989). As a consequence, the enormous potential of antenatal diagnosis to reduce the burden of genetic disease in the population, as well as the tragedy of recurrent cases within a family, is seldom realized. Fortunately, preimplantation genetic testing (PGT) now provides an approach in which antenatal diagnosis can be offered without incurring the adverse effects of the presymptomatic diagnosis. We believe this approach should be reviewed along with other relevant reproductive options when counseling patients at risk for Huntington disease and possibly other dominantly inherited traits as well.
PGT refers to a group of related technologies in which in vitro fertilization (IVF) is used to produce early embryos which are then biopsied, often as early as the 4 cell stage, to permit genetic testing of the embryos by PCR-based methods. Although the reliable amplification of target regions of the genome in single cells is still a technical challenge, prenatal diagnoses have been accurately made by this method without recognized adverse effects on the fetus (Harper & Handyside, 1994). For patients who are at high risk (typically 50%) of carrying a gene for Huntington disease, PGT offers a way in which they can participate in antenatal genetic testing without incurring the emotional, social and financial burdens that might result from the presymptomatic disclosure of their own carrier status. Such patients could be offered the option of having IVF with preimplantation biopsy and testing of their embryos without ever being informed of the specific test results. The couples would be told only that embryos were formed and tested, and that only apparently disease-free embryos were replaced in the uterus (and, if sufficient numbers were available, frozen for subsequent pregnancy attempts). The parents would specifically not be given any information about the number of eggs obtained, the number of embryos formed, the number surviving biopsy, the number in which diagnosis was successful, etc. In other words, no information would be given which might provide a basis for inferring whether or not any embryos with the Huntington gene were ever identified. Hence, parents would derive no direct or indirect information about their own genetic risk, while PGT, if performed accurately, could reduce the fetal risk to zero.
While we believe that this approach to the management of Huntington disease offers enormous potential benefits, it raises several important issues. First, it is apparent that IVF and PGT would be offered to some couples in whom the at-risk parent was actually unaffected and this could be construed as an inefficient or "wasteful" use of an expensive technology. However, since presymptomatic diagnosis is not the goal of the testing, redundant testing must be regarded as part of the cost of disease prevention by this approach. Second, accurate diagnosis on single cells removed from embryo biopsies is a technically challenging procedure, especially for other triplet repeat disorders such as fragile X (Black, 1994; Levinson et al., 1994; Ray and Handyside, 1995), and for dominant disorders where allele dropout is a particular risk. These concerns may be addressed through rigorous methodology such as the replacement of embryos only when the independent amplification of two blastomeres gives concordant normal results, or the possible use of blastocyst (multicell) biopsy. Third, scrupulous attention to confidentiality and careful genetic counseling with fully informed consent would obviously be required. None of these issues, however, would appear to be insurmountable.
In principle, the same conceptual approach may be applicable to other late onset dominant disorders such as Charcot-Marie-Tooth disease, certain familial cancers, and possibly even Alzheimer's disease. IVF and PGT would emerge as important approaches for the management of such diseases.
This proposal also has important public health implications. In Huntington disease, nearly all cases arise in pre-existing Huntington families rather than as new mutations. These procedures therefore constitute a potentially effective strategy for greatly reducing or even eliminating Huntington disease from the population. IVF is now a widely accepted reproductive option. On the average, 2-3 IVF cycles are required to achieve a live birth in the best programs. In the U.S., IVF with PGT is available for about $10,000 per treatment cycle, and less in some other countries. Hence, for an average cost of about $50,000, a couple containing one member at risk for having the Huntington gene could be on average assured of having two unaffected children and the risk of the disease in all future generations would be eliminated.
If this opportunity were to be provided on a voluntary basis to all at-risk couples, the gene frequency in the population could over several generations be dramatically reduced. The costs in any given generation as well as the cumulative benefits and cost savings to all future generations would be gradually realized.
In one of its crowning scientific achievements, mankind has succeeded in eradicating certain infectious diseases such as smallpox, which is now considered officially to be absent worldwide. Perhaps it is not too early to consider the elimination of Huntington disease and other extremely deleterious dominant traits as a goal for the 21st century. This proposal is based on our assumption that many patients at risk for Huntington disease would seize the opportunity to prevent transmission of the trait to their children if this could be done without disclosure of their own disease status. We do not know that our assumption is correct. but it is clearly a researchable issue that could lead to the initiation of voluntary programs to confirm the effectiveness and acceptability of PGT for this disease.
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