“Guidelines for Genetic Tests and Diagnoses in Medical Practice”
The Japanese Association of Medical Sciences(Footnote: This guideline was drafted by representatives of 17 medical
societies including the Japan Society of Human Genetics which had received
a request from The Japanese Association of Medical Sciences, and approved
on February 18, 2011.)
Introduction
The progress of medical genetics has made it possible to clarify the pathogenesis andclinical condition of monogenic (single-gene) diseases based on the identification of the
responsible genes. It has also led to the advancement in research aimed at thedevelopment of therapeutic strategies. Moreover, research on medical genetics hasbrought about broad achievements applicable in the fields of medicine and medical
practice such as the clarification of genetic factors associated with the onset of
multifactorial disorders, individual variations in pharmacological responses, and so on.
The techniques of genetic tests and diagnoses (genetic tests/diagnoses) developed in theprocesses have opened a new era when they can be utilized in all areas of medicine, andprovide appropriate selections in the treatments and preventive methods of diseases. In
this manner, genetic tests/diagnoses have become one of the most important medical
practices for physicians of all specialties. Meanwhile, special attention needs to be taken
in handling genetic information, since it does not change throughout the individual’s
lifetime, and could also affect their biological relatives (further referred simply as
relatives). An assumption underlying it is that diseases and clinical conditions based
upon genetic variations, and genotypes should be regarded as human diversities and not
as rare exceptions. Both human diversity and identity should be respected.
The Japanese Association of Medical Science (JAMS) considers that in orderto provide better medical care to the Japanese people, physicians, co-medicals andindividuals involved in genetic medicine should implement genetic tests/diagnoses
appropriately and effectively in medical practice, giving the highest attention to andthoughtful consideration in the characteristics of genetic information. JAMS proposes
here, in “Guidelines for Genetic Tests and Diagnoses in Medical Practice”, the basic
issues and principals that should be observed when implementing such genetic

tests/diagnoses.
Since genetic tests of diverse diseases and disease-groups have been carriedout in a wide range of medical fields or departments, genetic tests include certain points
to keep in mind that are unique to each case. Hence, it is recommended that each
medical society that belongs to JAMS should draw up guidelines or a manual for eachdisease (group), field or specialty, in accordance with these guidelines. Physicians andco-medicals involved in genetic test/diagnosis are requested to pursue appropriate
medical practices according to these guidelines.
Regarding genetic tests in research, they should be performed in accordancewith the guidelines related to the research.
1.

Scope of these guidelines

These guidelines shall apply to genetic tests of human genome/genes including
molecular genetic tests (DNA/RNA tests), cytogenetic tests, biochemical genetic tests(Note 1), and diagnoses using genetic information. The term “genetic tests” in theguidelines means those analyzing germline alterations such as mutations or
chromosomal abnormalities, or those related to germline alterations (Note 2).

In

medical practice, genetic tests are carried out not only for the diagnoses of patients who
have already developed a disease, but also for carrier detection, pre-symptomatic
diagnosis, genetic predisposition tests, pharmacogenetic diagnosis, prenatal diagnosis,
and newborn mass screening for congenital metabolic diseases.
Meanwhile, the guidelines do not cover genetic tests to identify genemutations, gene expression, or chromosomal abnormalities which are confined tosomatic cells such as cancer cells, because they occur after birth and will not be
conveyed to the next generation. However, the tests and diagnoses should refer to theseguidelines if there is a possibility that the results could be related to the germline genetic
information of the individual.
2.

The characteristics of genetic information; important issues for genetic testingand its use in diagnosis

Special attention should be paid to the following characteristics of genetic information
when a genetic test is performed and a diagnosis is made based on the test result.
 It does not change throughout the individual’s lifetime.

 It is partially shared with biological relatives.
 Genotype or phenotype of not only the individuals tested (further referred to as
examinees) but also their relatives can be predicted with a relatively accurate
probability.
 It is possible to make a diagnosis of non-progressive carriers (who will rarely develop
the disease in the future, but possess a mutated gene, and the mutation may possibly
be passed down to the next generation).
 It may be possible to predict the development of disease beforehand with almost
100% accuracy.
 It may be used for prenatal diagnosis.
 If it is inappropriately handled or disclosed, it may cause a social disadvantage to theexaminees and their relatives.
3.

Important points in the practice of genetic testing

When conducting a genetic test, it is necessary to understand that important points in thetest are different depending on the examinee and the purpose of the test. A list of the
explanatory items to be considered at the implementation is shown in Table 1.
3-1) Genetic testing for the diagnoses of patients who have developed a disease.
Genetic testing for the patients who have already developed a disease is conducted
mainly for the establishment of confirmed diagnosis that is highly suspected fromclinical information, or for the differential diagnosis that should be examined. The tests
are conducted if they are judged to be useful from clinical and genetic medical
perspectives after the deliberation of their analytical and clinical validity, and clinicalutility (Note 3). If an examinee requires multiple genetic tests, the scopes and the orderof the tests to be run should be thoughtfully determined from the clinical point of view.
At an appropriate time prior to the testing, the examinees should be informed about the
purpose and implication (including expected merits and demerits to the examinees) of
the tests as well as the possible conditions after the results will be obtained and the factthat the genetic information gathered by the tests may influence their relatives. The
directing physicians should confirm that the examinees have fully understood thesematters, and support their autonomous and independent decision on whether or not toundergo genetic testing. It is recommended to obtain a written informed consent fromthe examinees after the explanation and support. In principle, the examinee’s attending
doctor should perform the informed consent or assent before genetic testing, and if
necessary should arrange genetic counseling of an expert (Note 4) so that the examinee
can receive support for autonomous decision-making.
The results of genetic tests should be simply and clearly explained to theexaminees so that they can fully and adequately understand the results following a flowof diagnosis. A diagnosis should not be made from the result of genetic examination
alone, but be established comprehensively from the clinical and genetic information. Itshould be noted that genetic tests are helpful not only for the establishment of diagnosis,
but also for the medical practice using the information concerning genotype-phenotype
correlation brought about from the results. However, in the cases where it is difficult toestablish the pathologic significance of a novel mutation and where the penetrance ofdisease is considered to be less than 100%, special attention is required in theinterpretation of the results. When a confirmed diagnosis is established, it is importantto provide the patient with sufficient information concerning the progress, prognosis,
therapy and medical care of the disease.
3-2) Genetic testing for non-progressive carrier diagnosis, pre-symptomatic diagnosis
and prenatal diagnosis
The genetic tests performed for the purposes of non-progressive carrier diagnosis,
pre-symptomatic diagnosis and prenatal diagnosis should be conducted after anappropriate genetic counseling session (Note 4).
3-2)-(1) Diagnosis of non-progressive carrier
Non-progressive carriers do not develop a disease and thus normally require notreatment. Therefore, genetic testing of their diagnosis should not be done without theexaminee’s consent unless there is a special reason.
3-2)-(2) Pre-symptomatic diagnosis
In the case of a pre-symptomatic diagnosis that enables the prediction of diseasedevelopment beforehand with almost 100% accuracy, the genetic test(s) should be
performed after the examinee has sufficiently understood the information concerning
the available preventive method(s) and therapeutic strategies of the disease. On thedisclosure of test results, the examinee should be given full explanation about thecharacteristics and natural history of the disease again, and should be provided withappropriate medical information to maintain the examinee’s health. In particular, when
conducting a pre-symptomatic diagnosis of a disease for which preventive method(s)before, or effective therapies after the onset are unavailable, the care and support for theexaminee’s psychological health are indispensable before and after the test.
3-2)-(3) Prenatal diagnosis
Prenatal diagnosis, in a broad sense, includes methods involving cytogenetic,
biochemical and molecular genetics, as well as cytological and pathological methods,
using fetus samples such as amniotic fluid, chorionic villi etc.; pre-implantation genetic
diagnosis; and diagnostic imaging using ultrasound sonography. Because prenatal
diagnosis holds many medical, social and ethical issues to be considered, thetest/diagnosis should be performed complying with the views of the Japan Society of
Obstetrics and Gynecology and others, and after providing the examinee withappropriate genetic counseling (Note 4).
3-3) Genetic testing for a minor, or a person incapable of his/her own autonomous
decision-making.
In the case of genetic testing of a disease that has developed in a minor or a personlacking the ability to make his/her own autonomous decision, it is necessary to obtainthe consent of an individual standing as a surrogate representative. In this case, thesurrogate should decide after a thoughtful consideration of the examinee’s beneficencein his/her health care. It is desirable to obtain an assent from the examinee after giving
the explanation of the test at a level corresponding to the patient’s ability.
The same is true for genetic testing of diseases that develop before adulthood
if their pre-symptomatic diagnoses are useful in the management of the examinee’s
healthcare.
Meanwhile, genetic testing in a minor for the non-progressive carrier
diagnosis or the pre-symptomatic diagnosis of diseases that may develop in and afteradolescence should not be performed in principle by the consent from the examinee’ssurrogate, but should be postponed until the examinee reaches adulthood and becomesable to independently make a decision.

3-4) Pharmacogenetic tests
A pharmacogenetic test (Note 5) included in pharmacogenomic tests analyzes thegenetic variations in the germline. Because the genetic information obtained by the test
has the unique characteristics as undermentioned, the information can be dealt, in adifferent way from the genetic information of monogenic diseases, as ordinary clinicalinformation in medical practice by referring to the related guidelines (Note 5).
 It can be used to avoid drugs that bring about dangerous side effects or drugs that havelittle effect to the examinee.
 Appropriate dosing amount can be estimated.
 The estimating abilities of the phenotype based on genotype are not necessarily high.
3-5) Genetic testing for multifactorial diseases (genetic predisposition diagnosis)
An increasing number of genetic factors involved in multifactorial diseases have been
elucidated, and genetic tests for theses diseases to prevent their onset are expected to be
developed for clinical application. The tests used for the prediction of these
multifactorial disorders have the characteristics described below. It is necessary to
clarify the scientific grounds of the analytical and clinical validity, and clinical utility(Note 3) of the tests when they are implemented in clinics. Directing physicians should
also consider before the implementation how to provide genetic counseling (No.4) incase it is needed.
 Multiple genetic factors are involved in a complex manner in the development ofdiseases.
 The obtained result is the risk (probability) of the onset of disease.
 The power of prediction of phenotype based upon the genotype is not necessarilyhigh.
 Not only genetic factors but also environmental factors are involved in thedevelopment of disease.
 Contribution degrees of genetic and environmental factors differ for each disease.
4.

Handling of individual information and individual genetic information

Physicians and co-medicals accessing an examinee’s genetic information are required to
fully understand the characteristics of genetic information and handle individual genetic

information appropriately.
If a genetic test is performed for diagnosis of an examinee already showing
signs of symptoms, the test results should be recorded in the medical documents as anyother clinical test, and should be in principle shared by all physicians and healthcare
experts involved in the care of the examinee.
All individual genetic information obtained from genetic tests, as any othermedical information, is subject to confidentiality, and it should not be disclosed to any
third party including the examinee’s relatives without the consent of the examinee.
When the genetic diagnosis of an examinee is beneficial for the healthmanagement of the relatives of the examinee, disclosure of the genetic information to
the relatives may be considered if it is impossible to implement effective prevention andtreatment without such information. In principle, the consent of the examinee would benecessary in such cases. However, considering the best interest of the examinee’s
relatives, the examinee’s genetic information may be disclosed, even if the consent of
the examinee cannot be obtained. Disclosure to the examinee’s relative should be
performed not by the attending doctor’s sole judgment, but through consultation withthe ethics committee of the relevant medical institution.
5.

Genetic Counseling (Note 4)

In implementing genetic tests/diagnoses, genetic counseling is performed at an
appropriate time when necessary. Genetic counseling provides not only information, butalso psychological and social support so that the patient/examinee can autonomously
make a decision. Therefore, it is desirable that the attending doctor with clinicalexperience of the disease cooperates with an expert in genetic counseling, and they
practice as a medical team.
In case the content of genetic counseling can infringe on the privacy issue,
thoughtful response is required, for example, by describing and keeping the contents ofcounseling separate from the usual medical record.
Conclusion
In implementing genetic test/diagnosis, it is important that the attending doctors of eachclinical division should have enough understanding, knowledge and experience ingenetics. Because the information on genetic test/diagnosis is continuously updated, thedoctors involved are encouraged to keep up with the latest research results in order toutilize such information for their medical practice. It is desirable that they cooperatewith medical geneticists when necessary, taking into consideration the characteristics ofthe disease and the clinical area targeted for the genetic test.
It is desirable that medical institutes fully comprehend the aims and contentsof these guidelines, to continue education/enlightenment of not only physicians but also
healthcare experts and co-medicals involved in the genetic test/diagnosis regarding thebasic knowledge of medical genetics and the appropriate handling of individual genetic
information.

It is also desirable for medical institutes to construct a system forappropriate implementation of genetic medicine.
The field of medical genetics can make rapid progress and genetic testing is
expected to be broadly applied in various medical fields. There is a need for each
medical society that belongs to the Japanese Association of Medical Sciences to provide
education/enlightenment regarding the appropriate genetic medicine and genetic
counseling for the diseases in each medical area.
These guidelines are subject to occasional re-review.

(Note 1) Classification and definition of gene-based tests
Based upon the proposal of “Gene-related Test Standardization Experts Committee”
established in the Japanese Committee for Clinical Laboratory Standards (JCCLS), a
Specified Nonprofit Corporation, the term “genetic test” is classified and defined asfollows:
1) Pathogen genetic test (Nucleic acid test)
A test to detect and/or analyze the nucleic acid (DNA or RNA) of foreign pathogens(viruses and microbes including bacteria) that cause infection to humans
2) Human somatic cell genetic test
A test to clarify genetic information that changes along with the stage of the disease andis limited to the disease affected regions/tissues, including genetic test or gene
expression analysis to detect abnormal structure of the gene unique to cancer cells.
3) Human genetic test
A test to clarify genetic information within the genome and mitochondria which inprinciple does not change through the individual’s lifetime and is individually possessedby nature (information that is clarified by genetic analyses of the germline). This
includes genetic tests for monogenic diseases, multifactorial diseases, effects/side
effects/metabolism of drugs and information that could identify individuals.
1)-3) are collectively regarded as “gene-based tests”, and in general the terms
1) pathogen genetic test, 2) human somatic cell genetic test and 3) genetic test should be
used.
(Note 2) Germline mutation covered by these guidelines
There are two types of genetic mutations; namely germline mutations and somatic
mutations. The former is commonly present in all cells that form an individual, and canbe passed down to the next generation as genetic information. This mutation can bedetected by testing any cell that constitutes the human body, such as peripheral blood,skin fibroblast, hair, nail, and oral mucosa. The latter is a genetic mutation acquired insomatic cells after fertilization or birth, and it is not in principle passed down to the next
generation. They are mainly observed in malignant tumors. In order to detect thismutation, it is necessary to directly test the cancer cells or tissue. These guidelines cover
the genetic tests for germline mutations in principle.
Even if the tests are to detect differences in gene expression or chromosomal

abnormality that occurred within cancer cells after fertilization and thus will not bepassed down to the next generation, it is necessary to refer to these guidelines if it ispossibly related with the genetic information of the germline. However, forensic DNA
tests such as determination of parentage, which is not in the framework of medical
practice, is not covered by these guidelines.
(Note 3) Analytical validity, clinical validity and clinical utility
Analytical validity refers to, for example, a condition where the test method has been
fully established and appropriate quality controls have been performed for highly
reproducible results. The evaluation is based upon such information as the positive rate
when the subject has mutation, the negative rate when the subject has no mutation, thepresence of quality control program, the procedure of confirmation and so on.
Clinical validity refers to the condition that enough implications are given to
the test results. The evaluation is based upon such information as sensitivity (positive
rate when the examinee has the disease), specificity (negative rate when the examinee
has no disease), morbidity of the disease, positive predictive value, negative predictive
value, genotype-phenotype correlation and so on.
Clinical utility refers to clinical merits, i.e. the target disease can be diagnosedby the test, thereby obtaining information for the patient’s future prospects including
appropriate prevention and therapy. The evaluation is based upon the influence of thetest result to the examinee, and effective support to the examinee.
(Note 4) Genetic counseling
Genetic counseling is a process to help people understand and adapt to the medical,
psychological and familial implications of genetic contributions to disease. This processincludes the following: 1) interpretation of the family history and medical history toevaluate the probability of disease occurrence or recurrence, 2) education on the genetic
phenomena, test, management, prevention, resources and research and 3) informed
choice (autonomous decision with enough information) and counseling for thepromotion of the adaptation to risk and the actual condition.
At present, there are two institutions for the training of genetic counselors;“Japanese Board of Medical Genetics, Clinical Geneticist” <http://jbmg.jp/> targeting
medical doctors, and “Certified Genetic Counselor” <http://plaza.umin.ac.jp/~GC/>targeting non-medical doctors, both of which the Japan Society of Human Genetics andthe Japanese Society for Genetic Counseling cooperatively certify.
It is desirable that all medical doctors acquire basic knowledge and skills forgenetic counseling. Medical doctors and medical institutes involved in genetic
tests/diagnoses should be prepared to provide genetic counseling or introduce a genetic
counselor(s) when necessary.
(Note 5) Pharmacogenomic test and pharmacogenetic test
“The Terminology of pharmacogenomics” (Ministry of Health, Labour and Welfare)defines Pharmacogenomics (PGx) and Pharmacogenetics (PGt) as “a study on thevariation of DNA and the characteristics of RNA associated with response to drugs” and“a part of pharmacogenomics, and a study on the mutation of DNA sequence associatedwith response to drugs”, respectively. According to these definitions, not only the
analysis of the gene mutation of germline but also those of the somatic gene mutation oftumor cells and gene expression within cells are included in Pharmacogenomics (PGx).
Based upon the definitions described above, these guidelines define and cover
tests handling genetic information of germline in association with response to drugs aspharmacogenetic tests. The guidelines, associated with these tests include “theoperational guidelines of the pharmacogenomics test” and “the guideline for the clinicalresearch and test with the application of pharmacogenomics.”

Table 1. Examples of explanatory matters to be considered at the implementation of thegenetic test---------------------------------------------------------------------------------------------------------1) Disease name: The disease name and clinical condition targeted for the genetic test2) Epidemiological matters: Prevalence, morbidity, sex ratio, difference among
ethnicity, and so on3) Pathophysiology: Known or estimated molecular genetic mechanism of disease.
When it is unknown, indicate such fact.
4) Explanation of disease: Symptoms, age of onset, complications and accurate natural
course including prognosis
5) Therapy: Availability, effects, limitations or side effects of therapy, prevention, andearly diagnosis and treatment method (surveillance method)6) Genetic matters:
・ Mode of inheritance: Confirmed or estimated mode of inheritance・ Penetrance, mutation rate and probability of germinal mosaicism
・ Recurrence rate: Recurrence rate of the siblings and children (theoretical andempirical risk)
・ Genetic effect: probability that biological relatives are affected or carriers
7) Genetic test
・ Purpose of the genetic test (significance of genetic test for the patient who has
already developed disease): Name of the gene targeted by the test and its
characteristics, and so on
・ Method of the genetic test: Method for specimen collection, technology ofgenetic analysis and so on
・ Probability of definitive diagnosis by the genetic test: accuracy of the test,
difference in detection rate by the testing method, and so on
・ What more can be known by the genetic test: genotype-phenotype correlation
・ Disclosure method of the result of the genetic test: how and to whom the result
is disclosed
・ Possibility, outline and significance of non-disease carrier diagnosis,
pre-symptomatic diagnosis and prenatal diagnosis of relatives based upon theinformation obtained from the genetic test of the patient8) Information regarding social resources: medical expenses compensation system,

social-welfare system, patient support group information, and so on9) Availability of genetic counseling10) Characteristics of genetic information
・ Genetic information is partially shared among biological relatives
・ The results of genetic test performed for definitive diagnosis of a patient
already showing signs of symptoms should positively considered to bedisclosed to the relatives, when the obtained individual genetic information canbe beneficial for the relatives.
11) The rights of the examinee
・ The examinee is free to decide whether or not the examinee will receive thegenetic test, to discontinue the test, or to refuse the disclosure of the result.
・ The examinee will not receive any disadvantage in future medical care byrefusing or discontinuing the test, or refusing the disclosure of the result.
・ The examinee is presented with available options both before and after the test,
and the merits and demerits of each option are explained with easily
understandable terms.
----------------------------------------------------------------------------------------------------(Note: It does not necessarily follow that all the matters listed above should be
explained to an examinee before the implementation of the genetic tests. These arefor reference in explaining the test in accordance with the examinee’s degree ofunderstanding and characteristics of the disease.)Contributing Medical Societies and Members of the Drafting Committee
The Japan Society of Human Genetics: Yoshimitsu Fukushima (Chairperson), Naoyuki
Kamatani, Shinji Kosugi, Fumio Takada, Toshihiro Tanaka, Mariko
Tamai, Eiji Maruyama, Kaori Muto, and Yoichi Furukawa
The Japanese Society for Genetic Counseling: Yoshikazu Kuroki
The Japanese Society for Gene Diagnosis and Therapy: Kayoko Saito
The Japanese Society for Familial Tumors: Kazuo Tamura
Japan Society of Obstetrics and Gynecology: Fumiki Hirahara
The Japan Society of Pediatric Genetics: Kenjiro Kosaki
The Japanese Teratology Society: Hironao Numabe
Japanese Society for Inherited Metabolic Diseases: Torayuki Okuyama
Japanese Society for Mass-screening: Shohei Harada
Japanese Society of Laboratory Medicine: Hayato Miyaji
The Japanese Circulation Society: Makoto Nakazawa
Societas Neurologica Japonica: Shoji Tsuji
Japanese Dermatological Association: Daisuke Sawamura
The Oto-Rhino-Laryngological Society of Japan: Shinichi Usami
Japanese Ophthalmological Society: Noriyuki Azuma
Japanese Society of Hematology: Midori Shima
Japan Diabetes Society: Kishio Nanjo
Other Experts: Ryuichi Ida, Hiroshi Gushima, Mieko Tamaoki, Masayoshi Tsutsumi,
Toru Masui, Ichiro Matsuda, Takayuki Morisaki, Ryuichi Yamamoto,and Shohei Yonemoto
Collaborators: Akihiro Sakurai, Keiko Wakui, Rie Kawamura, Hideaki Sawai, Yasuko
Yamanouchi, Noriko Ando, Maiko Watanabe