The following subsections describe the regulatory landscape of PGT in the UK, Western Australia, and Japan. The first three subsections summarize the distribution of power over PGT in each country, respectively, in terms of the institutions and policy documents that can influence who may utilize PGT and under which circumstances. They also briefly summarize the medical indications for PGT, evaluation methods of PGT applications, and the review frameworks. The latter three subsections look at comparisons within each of these areas in greater detail.

PGT in the UK is regulated by the Human Fertilisation and Embryology Authority (HFEA). It was established by the Human Fertilisation and Embryology Act in 1990 [24] and oversees licensing and monitoring of clinics. All clinics and research centers dealing with human embryos need to be licensed under the HFEA and must comply with its rules and regulations [25]. Foundational laws regarding clinical application of PGT are laid out in the HFE Act. It states that PGT may be used when there is a risk that the child will be born with a serious disability, illness, or other hereditary medical condition [24]. More specific details regarding the application process can be found in the HFEA Code of Practice [26] and on online web pages oriented toward informing the public about treatment options [27]. In these documents, the HFEA establishes clear guidelines for both the designated testing centers and the public. However, the HFEA does not play a direct role in the decision-making process of each individual case. Instead, the HFEA maintains a list of over 600 conditions that have been pre-approved for PGT in general. This list is easily accessed from the HFEA’s online webpage [27] and serves to inform both the testing centers that are licensed to carry out PGT as well as members of the public who may be considering PGT as an option. If the condition for which PGT is to be used is on the list, those seeking PGT can be referred to a regional clinical genetics service by their general practitioner. The final decision on the appropriateness of the procedure is made through discussion between designated physicians at the testing center and those seeking treatment. During this decision, the testing center must consider a set of medical and social factors as designated by the HFEA Code of Practice [26]. The HFEA itself is not directly involved in each individual application for PGT unless it is regarding a condition that has not yet been added to their pre-approved list. In this case, the designated testing center makes an application to the HFEA on behalf of those seeking treatment. The HFEA then refers to the aforementioned set of medical and social factors to decide whether the condition should be added [26]. In other words, the HFEA’s pre-approved list serves as the primary foundation on which decisions are made.

PGT in Western Australia is regulated broadly at the national level by guidelines from the National Health and Medical Research Council (NHMRC) [28]. At the state level, PGT falls within the jurisdiction of the Reproductive Technology Council (RTC). The RTC has the power to establish rules of practice and provide recommendations to the Western Australia Department of Health [29]. Like the UK case, foundational laws regarding PGT in Western Australia were laid out by the Human Reproductive Technology Act in 1991. In regard to PGT, section 14(2b) states that ‘the [RTC] may not grant approval to any diagnostic procedure to be carried out upon or with a human embryo unless… where the diagnostic procedure is for the genetic testing of the embryo, there is a significant risk of a serious genetic abnormality or disease being present in the embryo’ [30]. Further details are specified by the RTC’s guiding policy document on embryo-related procedures, the Policy on Approval of Diagnostic Procedures Involving Embryos [31]. An online informational pamphlet aimed at informing the public also exists to provide additional information [32].

Each individual PGT application must be approved by the RTC on a case-by-case basis. Decisions are made based on a set of medical and social factors relating to the individual circumstances of those seeking treatment. The factors that must be considered during these decisions are designated by the RTC under the guidance of the NHMRC’s suggestions [31]. Maintaining a pre-approved list of possible genetic conditions for which PGT may be utilized does not exist, as it has been pointed out that ‘it is not possible to list the genetic conditions, diseases or abnormalities for which the use of PGT is ethically acceptable, as context is important and the assessment may change over time’ [33].

PGT in Japan is overseen by the Japanese Society of Obstetrics and Gynecology (JSOG). While the JSOG does not have explicit legal power, clinics that use reproductive technologies are obliged to follow the JSOG’s guidelines. Failure to do so may result in a loss of membership and therefore the ability to practice reproductive medicine [34, 35]. The JSOG made its first statement on PGT in October 1998, by stating that PGT was permitted but limited to testing for ‘serious’ disease only. An ethics subcommittee was created to evaluate the circumstances of those seeking treatment on an individual case-by-case basis [36]. Until recently, guidelines for PGT stated that a serious disease was one that significantly impairs the daily life or threatens the survival of the child before reaching adulthood. Significant impairment to the daily life of the child was understood as a severity level where the said child was unable to sustain life without use of a ventilator. Based on this definition, additional factors that were taken into consideration include the penetrance rate (likelihood that the genetic abnormality will manifest as clinical symptoms), the expected age of onset, and the severity of symptoms, the number of family members that have the condition and the level of severity of their symptoms, and the possibility of treatment [36, 37].

Policy revisions for the standard for disease severity in Japan began after the JSOG received an application in 2019 from a patient with retinoblastoma seeking PGT, whose condition did not meet the interpretation of a serious disease at the time, but from other perspectives could be thought to significantly impair the daily life of the child [36, 38]. The inherited form of retinoblastoma follows an autosomal-dominant inheritance pattern, meaning only one parent needs to be a carrier for there to be a 50% chance of passing on the defective gene to their offspring. Early detection is crucial for effective treatment, and as such genetic testing may be recommended to determine the child’s risk of developing this condition [39]. Various concerns were voiced during the review process of the patient’s application, the two strongest ones being (1) that part of the standard for disease severity was based on whether age of onset was before adulthood and (2) whether it was sufficient enough for the debate on the seriousness of the retinoblastoma case to be carried out by a committee that was composed of only medical doctors, rather than one that included experts from diverse academic fields to provide broader perspectives from ethical and social viewpoints [36]. Although some argued that retinoblastoma was serious enough due to its impact on the daily life of the future child, opposing concerns were raised that if PGT were to be approved for this case, the use of PGT for non-life-threatening conditions would increase [36, 38].

The dilemma of the retinoblastoma case prompted the JSOG to reflect on the fact that the current standard for disease severity for PGT was based only on medical criteria. As a result, it was seen as necessary to revise the standard while considering a broader range of factors that contribute to the lived realities of genetic diseases and conditions. Included in discussions during the revision process were a diverse range of participants that included medical, humanities, and social science professionals as well as patient groupsFootnote 3 and members of the public. The meetings were also open to online viewing and to commentary from the public [36].

Underlying the discussions was the awareness of the potential negative social impact that PGT can have on the lives of people currently living with genetic conditions. Stakeholders that were against expanding the applications of PGT by removing the ‘before adulthood’ indication voiced that such a revision, e.g., opening the possibility for including adult-onset diseases, would make it more difficult for people currently living with genetic conditions to have fulfilled lives [40]. It was stated that the goal moving forward should be to strive toward a society where all people, whether they have a disability or not, can live healthy lives (shougai ga aru kata mo nai kata mo, dare mo ga kenkou ni ikirareru yo no naka; 障碍がある方もない方も、だれもが健康に生きられる世の中) and that moving forward, there is a need to sustain multidisciplinary discourse through the collaboration of experts of the medical field, ELSI disciplines, individuals and families who have been affected by the genetic condition in question, and patient groups [37]. The final report on this matter sets the standard for disease severity as the following:

[A serious disease in this context is,] as a general principle, a condition that causes symptoms that strongly impair daily life or threaten the survival before reaching adulthood, and for which there is no effective treatment to avoid such symptoms, or for which highly advanced and invasive treatment is necessary [36].

Although discussions had been moving toward a consensus about removing the indication of age of onset of ‘before reaching adulthood,’ ultimately the committee decided to leave it in based on the thought that the JSOG should not promote PGT, but rather act based on the individual circumstances of each case [36]. At the same time, considerations for conditions that manifest after adulthood resulted in the following addition to the statement:

When making a judgement on a case for which there has been no review experience, it is necessary to request the opinion of an expert group (clinical or genetic) … where the opinion is based on a medical perspective… but also takes into consideration the lifestyle background and thoughts of the couple seeking treatment [36].

In other words, the discussions resulted in a form of compromise. The new definition does not completely open up PGT for all conditions regardless of age of onset; however, the addition of ‘as a general principle’ (gensoku to shite; 原則として) provides the flexibility to make exceptions under certain circumstances. Furthermore, in the case that an application is declined based on the opinion forms submitted by the expert groups indicated above, it is possible for those seeking treatment to re-apply and be evaluated by a clinical ethics review committee, initiated by the JSOG, that is comprised of diverse stakeholders such as members of patient groups and non-experts from the public.Footnote 4 The revision thus suggests a shift toward more inclusive policy-making and greater awareness of the diverse circumstances related to living with a genetic condition.

For all cases, the term serious (juutoku; 重篤 in Japanese JSOG policy) is used to describe the circumstances under which PGT may be applicable (Table 1). This is consistent with previous literature that has described the status of PGT in various countries [7, 9, 16, 23, 35]. An additional point of similarity is the specification that the targeted genetic or abnormality should be one that manifests as clinical symptoms in the child. This specification is important because it indicates that the target that PGT is meant to avoid is not the genetic abnormality itself, but rather the symptoms, impairment, or suffering with which the genetic abnormality is associated in children. At the same time, each case shows subtle differences. Western Australia explicitly states that a ‘genetic abnormality or disease in the embryo is not simply a defect in the genetic material, but is one associated with a known clinical deficit’ [31]. While this is implied in the indications of the UK and Japan, Western Australia shows explicit clarification. Additionally, the UK does not use the term disease. Instead, it is substituted for disability, illness, or medical condition. This wording is in-line with the preferred language of disability groups [41]. The UK is also the only jurisdiction in this study to include mitochondrial abnormalities.

Each jurisdiction in this study employs a different evaluation method when handling applications for PGT. Evaluation methods refer to the combination of decision-making frameworks that are utilized by the designated institution to approve or reject PGT applications. These may include a pre-approved list of conditions, case-by-case review, and the more specific review frameworks that are employed during any case-by-case review (Table 2).

The evaluation methods in Japan and Western Australia are similar in the sense that they both rely mainly on case-by-case evaluation by the designated institution. In Japan, the JSOG uses an overarching definition statement to set the standard for a serious disease, the risk of which would indicate PGT. The statement itself emphasizes the main factors that should be considered, while a short list of additional factors is noted separately. Based on these factors, the JSOG approves applications from those seeking treatment on a case-by-case basis.

In Western Australia, the RTC utilizes a list that includes both medical factors, which are based on the profile of the genetic condition to be tested for, and social factors, which are based on the individual circumstances of those seeking treatment. These factors are divided into hierarchical distinctions, where some are labeled as ‘essential’ to the evaluation process, while others are labeled as ‘desirable.’

Unlike the previous jurisdictions, the HFEA in the UK maintains a list of over 600 pre-approved conditions that are thought to be serious enough for PGT. Under the circumstances that the HFEA must review an application for a genetic condition that has not yet been added to the list, their review framework is based on a list of medical and social factors, like the RTC in Western Australia. However, there is no distinction between factors that are essential versus those that are desirable. Furthermore, due to the significant volume of conditions that are already on the pre-approved list, it is more likely that the final decision will be left to the physician at the designated testing center of those seeking treatment. To the best of our knowledge, the UK is the only country to utilize a pre-approved list of genetic conditions for PGT.

Further differences were identified within the specific medical and social factors that are indicated by the review frameworks of each evaluation method (Tables 3, 4). Common factors across all three jurisdictions in this study are the medical factors which are related to the potential impact on the daily life of the child and the availability of treatment for the condition. Review frameworks by the HFEA and RTC include both medical and social factors (Table 3). In these cases, it is common to refer to the support that would be available for the future child and the views of the family. Factors that are included in the review framework of the JSOG are noticeably fewer, yet broader than those of the HFEA or RTC. This is likely due to the fact the factors are embedded within an overarching definition statement on disease severity rather than being presented in a list format. Compared to the other two institutions, the JSOG appears to put a particular emphasis on the impact a condition will have on the everyday life of the child, i.e., the quality of life (QOL). The definition statement itself refers only to medical factors. Social factors are indeed considered as well; however, they are indicated as supplemental factors or factors to be considered in exceptional cases (Table 4).