Ethics when genotype under-determines clinical phenotype

- Norio Fujiki and Kozo Hashimoto
Medical Advisor, and Head, TOYOBO Tsuruga Gene Analysis Laboratory, Tsuruya, 914, JAPAN

Eubios Journal of Asian and International Bioethics 6 (1996), 173.
Genetic analysis and its application to human diseases are still in their infancy. But more genes are being discovered all the time for diagnosis and treatment. These identify the risk of disease but present ethical dilemmas, which require speedy resolution to keep up with advancing technological processes.

Our laboratory has done routine work on trinucleotide repeat diseases as well as DNA polymorphism and infectious disease, as shown in Table 1. Technological problems that required resolution included; 1) expensive reagents and laborious techniques for DNA extraction; and 2) contamination of PCR amplification and labile quality control.

Table 1: Tests in Toyobo Tsuruga Gene Analysis Laboratory
Trinucleotide repeat diseases: (Numbers since 1993/*1995)
DyM 794
SCA1 73*
MJD 127*

DNA polymorphism identification
ACE 1100*
ApoE 280*
AGT 290*
CETP 35*

Viral and bacterial pathogens
HCV 2279
HBV 115
TB, cytomegalovirus, Chlamydia 207*

Other analyses occasionally performed include individual identification and cancer related genes.

First of all, our cost for analysis of trinucleotide repeat mutation requires at least 50,000 yen (approximately US$450) per item, due to expensive reagents, with abundant manpower, especially for DNA extraction processes. So we have tried modifications using low cost reagents and developing new techniques using the telomeric repeat PCR amplification protocol, which continues PCR amplification in a single tube, for the important role on cancer and aging processes. We have improved the Shay technique for telomerase determination using non-RI and avoiding contamination of PCR amplification and for isolating base primers with a wax barrier.

For quality control, we have joined the quality control survey of the College of American Pathologists, and also intralaboratory and interlaboratory surveys in the Japanese Society of Gene Diagnosis and Therapy, using positive and negative control samples. We also obtained patent licenses from Roche Laboratory for PCR techniques.

We have performed analysis upon requests by doctors, not directly by patient themselves. But we have always asked users about bioethical confirmation, that they should be professional in medical genetics, obtain informed consents before their order, and make an exact family pedigree of patient and families, for the confirmation of laboratory data with family pedigree. Double checking and storing for a given period (after that time we should discard) is absolutely necessary, as well as privacy protection by numbering without name. We should also report only electrophoretic patterns with photo to users, and have further discussion with medical advisors and the head of the laboratory, if we have any question from the user. Anyway, we have confirmed there is a good staff-patient relationship between patient, doctor, nurse and laboratory staff for bioethical understanding, such as protection of privacy etc.

During my long services in medical genetics, especially genetic counseling (2), I have had many difficult problems, especially in the psychiatric and psychological fields: on one side, monogenic and molecular studies, and on the other side, polygenic and linkage study. The goal of the human genome project is the sequencing of the entire human genome. We have to determine the variability of the gene between individuals, and to determine how this variation contributes to phenotypic differences. For complex traits, such as common diseases, psychiatric and behavioural diseases, this will be facilitated by a merger between polygenic and molecular genetics.

Genetic testings are divided into two groups, monogenic and polygenic anomalies, such as thalassaemia and cystic fibrosis as single gene analysis, and such as diabetes, hypertension, Alzheimer disease and other common diseases, which are clarified by linkage analysis and multi-gene analyses. Especially, with the latter, the individual genetic predisposition modified by life style should be explained, considering the different frequency of RFLPs in Japanese population, and not considering that the positive results of gene testing equals the onset or diagnosis of the disease in question directly. The former should be considered carefully given the genetic heterogeneity and variable clinical symptoms, such as anticipation, variability and expressivity. These should be analyzed for further collection of laboratory data and clinical features.

For example, Alzheimer's disease is a neuronal degeneration process due to the accumulation of amyloid precursor protein, which is coded for by a gene located on chromosome 21q for familiar Alzheimer disease. However, there have other types located on chromosome 14 and 19. We have noticed the gene coded ApoE in chromosome 19q, which is related with amyloid precursor protein. Compared with ApoE2 related with familial hypercholesterolemia, ApoE4 homozygote has a strong link with sporadic Alzheimer's disease more than heterozygotes, who are more than normal homozygotes. This means Alzheimer's patient have 1.8 times higher frequency of ApoE4 gene than normal, thus ApoE4 is not the gene coding Alzheimer disease itself, but only one of the genetic factors determining susceptibility (high risk factor) for Alzheimer's disease. This case is similar to gene combinations and environmental risk factors in common diseases. We have always carefully explained such complexities during genetic counseling for common diseases.

The fact that DNA analysis often reveals only a "high risk" of genetic disease without predicting the disease with certainty, poses a major challenge to the ethics of the new genetics. Revealing genetic information to the patient can lead to fear, nervousness and other psychological stress. The psychosomatic effects of this stress might be more dangerous to the patient than the genetic factor itself, especially when the genetic factor is not a certain predictor but only a high risk factor.

In such a sensitive doctor-patient situation, the old and simplistic principles of bioethics, "autonomy", "informed consent", and "privacy" are not sufficient as practical guidelines. The profession of medicine will have to join forces with molecular biology, social work, nursing, anthropology and psychology to find new solutions to new problems. The "right not to know" will be of major importance. To conclude, we have emphasized the protection of privacy, informed consent, self-decision making for counselee and training, and knowledge of clinical genetics for counselor and laboratory staff, including quality control with licensed laboratory staff. For this reason, as described in the JSHG guidelines for genetic counseling, prenatal diagnosis and gene diagnosis (4) we have emphasized: 1) informed consent, such as for the purpose of testing, procedure, quality limitation and accessibility for genetic heterogeneity; 2) respect of the right to know, not to know and not to want to know etc.; 3) autonomous decision making of the client and their family.

Finally, we have emphasized the need to educate clinical doctors, nurses and laboratory staff, as well as the general public, and it should be necessary to have social agreements for privacy protection and biotechnology assessments.

1. Fujiki, N. DNA diagnosis in commercial laboratory (Japanese).
2. Fujiki, N. Medical geneticist's responsibility. Proceedings of the Second Session of the International Bioethics Committee of UNESCO, 2 (1995), 15-20.
3. Perick-Vance, MA. et al. Linkage studies in familial Alzheimer's disease. AJHG 48 (1991), 1034.
4. Matsuda et al. Guidelines for Genetic Counseling and Prenatal Diagnosis (1994); Guidelines for Genetic Testing, using DNA analysis (1995) - Japan Society of Human Genetics EJAIB 6 (1996), 137-8.
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