The ethical questions related to the proper management of incidental findings (IFs) in the context of genomic research or clinical testing are often complex and multi-layered. Dealing with this genre of intricate bioethical issues, like genetic engineering and reproductive technologies, necessitates developing a comprehensive and consistent ethical framework. The delineation of such a framework is crucial to illustrate that the moral assessment of a particular course of action, whether deemed acceptable or unacceptable, is founded on robust and consistent reasoning rather than subjective biases. Moreover, such a framework plays an indispensable role in bridging gaps between diverse moral traditions, aligning with a primary objective of this study—fostering constructive dialogue. This approach aligns with the advocacy of Muslim ethicists who emphasize the imperative to evolve a comprehensive discourse in contemporary Islamic bioethics transcending mere legal boundaries (Sachedina, 2008, p. 244). Thus, the ethical management of IFs serves as an exemplar to show how discerning the theoretical underpinnings of a governing framework can facilitate the systematic and consistent evaluation of specific and concrete bioethical issues.

Against this background, the main question to be addressed reads: What features make an ethical framework comprehensive enough to effectively address intricate bioethical issues such as incidental findings (IFs), genetic engineering, and reproductive technologies? In mainstream secular bioethical discourse, the late bioethicist from Georgetown University Robert Veatch (d. 2020) offered a well-reasoned proposition in his seminal work, The Basics of Bioethics. Veatch argued that a thorough and consistent bioethical analysis should encompass four main levels of moral discourse:

  • Metaethics (First Level): This is the most abstract level that delves into the fundamental questions of ethics and their ultimate grounding, exploring issues such as the sources of ethics and the methodologies for ascertaining correct answers. Veatch noted that religious traditions often exhibit a particular interest in this level, and most of them have developed standard approaches to address such metaethical questions.

  • Normative Ethics (Second Level): Here, the examination extends to broad norms of behavior and character. Lists of moral principles and values are articulated within this level, serving as ethical criteria for evaluating actions. Additionally, lists concerning character traits judged as morally praiseworthy are considered.

  • Rules and Maxims (Third Level): This level involves the formulation of general rules, rights, and maxims which are applicable to a wide range of cases. Occasionally, specific groups of these rules and maxims are consolidated into codes of ethics.

  • Casuistry (Fourth Level): At the most granular level, the focus shifts to concrete and individual case problems. This involves seeking morally appropriate behavior in a particular situation. Agreements on the morally acceptable course of action in a specific situation (fourth level) may be reached even when consensus is lacking at other levels, especially the first one (Veatch, 2012, pp. 2–9).Footnote 1

As far as the Islamic moral tradition is concerned, the extent of comprehensiveness in contemporary bioethical discourse is typically gauged by its level of engagement with diverse scholarly disciplines and genres both inside and outside the Islamic tradition (Moosa, 2007, pp. 47–59; Padela, 2021, pp. 227–234; Sachedina, 2008a, 2008b, 2009, pp. 7–14; Setia, 2022, pp. 79–109).Footnote 2 Given the nature of this study, which aims to forge connections between various bioethical discourses, a synesthetic and hybrid ethical framework will be introduced. This proposed framework seeks to amalgamate Veatch’s multi-layered structure and the recommendation of Muslim ethicists to involve different disciplines.

Consequently, the first three levels of Veatch’s multi-layered framework—metaethics, rules, and normative ethics—will be consolidated under the heading “Theoretical level: Metaethics and normative ethics.” The fourth level, casuistry, will be explored independently under the heading “Practical level: Fivefold classification of human acts.” Each of the two sections dedicated respectively to the theoretical and practical levels will incorporate pertinent insights from various Islamic scholarly disciplines and genres. These disciplines include theology (ʿaqīda), legal theory (uṣūl fiqh), jurisprudence (fiqh), and Sufism. Additionally, a diverse array of scholarly genres will be consulted, encompassing works on regulating public morality through the institution of ḥisba (professional accountability), etiquettes of the physician (adab al-ṭabīb), and more.Footnote 3

Theoretical Level: Metaethics and Normative Ethics

Metaethics

The grand metaethical questions are primarily examined within two main scholarly disciplines in the Islamic tradition: theology (ʿaqīda) and legal theory (uṣūl al-fiqh). The foundational premise revolves around an individual’s deeply ingrained conviction and belief in the existence of One God, characterized by flawless attributes and reflected in His names—attributes that encompass omniscience, omnipotence, justice, wisdom, mercy, and more.Footnote 4 This recognition of God’s immaculate character, compared to the inherently limited cognitive capacity of humans, leads to the acknowledgment of humanity’s need for divine guidance. This guidance is perceived as essential for achieving success in this life and salvation in the hereafter.

The divine guidance necessary for human conduct is conveyed to humans through scriptures revealed to prophets and messengers. These chosen individuals are entrusted with the task of elucidating to humanity what God desires—referred to as God’s will (murād Allāh)—and providing guidance on how individuals should comport themselves in alignment with this divine will.

In their pursuit to comprehend the overarching philosophy underlying God’s will and the ways to distinguish between good/benefit and bad/harm, Muslim scholars endeavored to formulate a list of objectives for both God’s creation and God’s legislation. Concerning the former, scholars articulated three objectives for which humans were created by God: the cultivation of the earth (ʿimārat al-arḍ), worshipping God (ʿibāda), and functioning as God’s trustee and vicegerent on earth (khilāfa). The closer an individual aligns with these objectives, the more morally upright they become (Aṣfahānī, 2007, pp. 82–83). Regarding the latter, scholars held that an examination of the religio-ethical system of Islam reveals five higher objectives of Sharia (maqāṣid al-Sharīʿa): safeguarding religion, life, wealth, intellect, and offspring. A number of modern studies have explored the relevance of these higher objectives to the field of bioethics (Ghaly, 2016; Rafīʿ, 2012; Shīwa, 2020; Zūzū, 2002, pp. 167–201).

Within this broad theological framework, Muslim legal theorists and jurists formulated the concept of khiṭāb Allāh, loosely translated as God’s address, which is primarily conveyed through the Quran and Sunna, both integral to understanding this divine communication. The Quran is believed to be the literal word of God and the Sunna comprises statements, deeds, and approvals attributed to the Prophet of Islam, who God has assigned the task of explaining His revelation to humanity.Footnote 5 All religious commandments, encapsulated in the comprehensive term taklīf, establish the relationship between God, as the divine addressor (mukhāṭib), and man, as the human addressees (mukhāṭab).

In God’s justice toward the human addressee, certain senses, faculties, and capacities have been provided to enable humans to comprehend and fulfill God’s commandments. The extent and magnitude of these obligations are intricately linked to an individual’s mental capacity (istiṭāʿa ʿaqliyya), enabling comprehension of the divine address’s meaning, and physical capacity (qudra badaniyya), facilitating the execution of commandments. Full functionality of mental and physical powers entitles individuals to the complete package of religious obligations and duties (taklīf), as these powers constitute the foundational elements of legal capacity (ahliyya). The scope of religious obligations and duties automatically diminishes when either of these two types of power is deficient or malfunctions (Ghaly, 2019, pp. 259–260; Sarakhsī, n.d., vol. 2, p. 340; Samʿānī, 1999, vol. 2, p. 373).

Against this background, the overarching question that Muslim scholars grapple with, in their quest to judge an act as good or evil, reads: Is the act in conformity with God’s will (murād Allāh)? If the answer is yes, then the act is good, and if no, the act is viewed as bad or evil (Ibn Ḥazm, 1983, vol. 1, p. 8; Juwaynī, 1996, vol. 1, pp. 154, 235; Shirāzī, 2003, p. 127). Muslim religious scholars concluded that the governing framework and the grand rule in this regard is that God primarily wills achieving the good/benefit (maṣlaḥa) and averting the bad/harm (mafsada); both in this life and in the hereafter (Qarāfī, 1980, vol. 1, p. 120; Shāṭibī, 2003, vol 1, p. 17, vol. 4, p. 346).

Muslim scholars use the technical term mukallaf, which literally means someone charged with certain duties, to refer to a person with recognized legal capacity. In secular bioethical terms, mukallaf comes close to, though not identical with, the term “autonomous person” or someone who possesses autonomy. Autonomy entails the right to make decisions reflecting one’s values, preferences, and sense of self (Veatch & Guidry-Grimes, 2020, pp. 133–134). Essentially, both terms denote the right to decide the proper course of action and the moral responsibility for the decisions taken. In the case of a mukallaf, however, the scope of autonomy is voluntarily restricted by one’s belief in God and acceptance of the principle that God knows what is genuinely beneficial or harmful in this life and the hereafter. In this sense, one’s voluntary submission to God’s will and the sincere intention to act accordingly (imtithāl) are values in themselves, separate from one’s ability to discern the underlying benefits in obeying God’s specific commandment or one’s eventual success or failure in implementing this divine will (ʿAtiyya, 2003, p. 109; Juwaynī, 1996, vol. 1, pp. 159, 442; Shāṭibī, 2003, vol. 2, pp. 171–289, vol. 3, p. 101).

In this context, medical intervention in one’s body necessitates not only the consent of the autonomous patient but also God’s permission in the first instance. The legitimacy of a respective person’s right to accept or reject a specific medical intervention is contingent upon God’s permission to do so. Therefore, inflicting unjustified harm to the body or actively terminating one’s life are unethical practices, even if they were performed on the basis of informed consent that was voluntarily provided by an autonomous person (Bārr, 2005; International Organization for Islamic Medicine, 1981, pp. 30, 53–55; Shāṭibī, 2003, vol. 3, pp. 102–104; Sharaf al-Dīn, 1983, pp. 48–51). Further details on the ramifications of this point and its relevance to the ethical management of IFs will be outlined below, particularly in reference to instances where information disclosure will be judged as obligatory.

Normative Ethics

The above-outlined metaethical framework has been the foundation for centuries-long deliberations within the scholarly community of Muslim scholars on how individuals should align their behavior in various aspects of life with this broad framework. Within the disciplines of Islamic legal theory and jurisprudence, a rigorous and complex system has been developed to demonstrate how relevant references in the primary sources of divine guidance, namely the Quran and Sunna, can be employed to address people’s questions.

One of the key terms in this regard is the concept of ijtihād (independent religio-ethical reasoning), an Arabic term that literally denotes exerting one’s utmost effort or unsparingly utilizing one’s power and ability. As a technical juristic term, ijtihād involves the exertion of one’s utmost effort (istifrāgh al-wusʿ) by a qualified specialist to discern the will of God in a particular situation and determine how the discovered will should be implemented. In the quest to understand how God wants humans to behave in specific circumstances, the practitioner of ijtihād, known as a mujtahid, begins by consulting the two scriptural sources, namely the Quran and Sunna, considered the primary repositories of information about God’s will. Additionally, Muslim scholars have developed a wide range of secondary sources, the scope and validity of which in the reasoning process have been the subject of discussions and disagreements throughout history. The utilization of secondary sources in the ijtihād process becomes essential when the scriptural sources do not provide direct or conclusive answers about how to understand or implement God’s will regarding novel questions (Juwaynī, 1996, pp. 311–422; Qaraḍāwī, 1996; Weiss, 1978).

Through the recurrent and systematic practice of ijtihād over centuries, which has scrutinized a large number of cases and issues, several grand rules or maxims have emerged. These maxims serve as principles to which Muslim jurists across different schools appeal when facing new cases or unprecedented questions (Kamali, 2006; Musa, 2014; Zakariyah, 2015, pp. 24–79). As many bioethical questions are novel, an increasing number of modern works have explored the relevance of these maxims to medical practice in general or to specific bioethical issues (Abū Ghudda, 1984; Al-Nomay & Alfayyad, 2015; Dusarī, 2016; Elgariani, 2012; Ghaly, 2015, pp. 28–29, 32–33; Sharīfa, 2018; Sharaf al-Dīn, 1982).

Islamic institutions with an interest in the field of bioethics have played a crucial role in developing significant ethical codes and accessible reference works for interested healthcare professionals. Notable examples include the Islamic Code of Medical Ethics (Al-Dustūr al-Islāmī li al-mihan al-ṭibbiyya), issued in 1981, and the International Islamic Code for Medical and Health Ethics (Al-Mīthāq al-Islāmī al-ʿālamī li al-akhlāqiyyāt al-ṭibbiyya wa al-ṣiḥḥiyya), released in 2004. The two documents are available in both Arabic and English (International Organization for Islamic Medicine, 1981a, 1981b; Gendy & Awadi, 2005; Jundī & ʿAwaḍī, 2005). Besides presenting more than 100 articles, articulated in a semi-legal language, delineating Islamic perspectives on a wide range of issues (Jundī & ʿAwaḍī, 2005, pp. 55–127), the 2004 Code extensively engages with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, as issued by the Council for International Organizations of Medical Sciences (Jundī & ʿAwaḍī, 2005, pp. 135–289).

In addition to delineating the principles of morally right action, Islamic normative ethics extensively examines the character of the actor or agent, particularly the physician or healthcare practitioner. Both early and modern works authored by physicians and religious scholars delve into the question of which character traits or virtues contribute to making a physician good or virtuous. These works often intertwine the requisites for both professional excellence and virtuous character, emphasizing that both aspects are essential for the development of a “good physician.” Some of these works fall within the genre of adab al-ṭabīb (etiquettes of the physician) (Abū Ghudda, 1981; Bārr & Sibāʿī, 2009; Levey, 1967; Ruhāwī, 1992). Additionally, works from other genres such as ḥisba have also contributed to these discussions (Abū Ghudda, 1981, pp. 161–162; Qurashī, 1976, pp. 247–259; Subkī, 1986, p. 103).

Practical Level: Fivefold Classification of Human Acts

Casuistry represents the most practical level in moral discourse, involving the ethical evaluation and normative judgment of concrete scenarios and specific actions. To systematize this level, both secular and religious moral discourses have sought to develop schemes or scales for classifying human acts based on their ethical value. These frameworks aim to determine the degree of goodness or badness associated with specific acts. In an effort to maintain a bridge between secular and Islamic bioethical discourses, this section begins with concise notes about the secular deliberations on this issue.

In moral philosophy, the standard threefold scheme for the classification of actions posits that actions fall into one of three main categories, namely (a) obligatory, (b) prohibited and (c) permissible or morally neutral. Actions which are deemed morally required belong to the first category, those which are morally condemned fall into the second category and the actions which do not fit into either of the first two categories are considered neutral and shall make part of the third category. In his article “Saints and Heroes” published in 1958, J. O. Urmson (d. 2012) made a pioneering argument in modern non-religious moral philosophyFootnote 6 for the inclusion of a fourth category, namely (d) supererogatory. This fourth category would encompass heroic or saintly self-sacrifices which go beyond the bounds of duty like the doctor who volunteers to help in a foreign, plague-ridden city. Despite Urmson’s critique, some moral philosophers continued defending the veracity of the traditional tripartite classification scheme of actions. However, the new fourfold categorization of moral acts (obligatory, prohibited, supererogatory and permissible) proved to be more appealing to the extent that some moral philosophers even described it as approaching the status of “near dogma” (Guevara, 1999, pp. 593–624; Hedberg, 2014, pp. 3623–3624) finding its way into standard works on bioethics (Beauchamp & Childress, 2013, p. 45). Innovative classification, however, coexists with the traditional tripartite scheme, which has not been entirely abandoned or deemed obsolete. The traditional tripartite classification continues to be employed in certain bioethical discussions, including those pertaining to the ethical management of incidental findings (IFs) (Presidential Commission for the Study of Bioethical Issues, 2013, pp. 84–85).

As far as the Islamic tradition is concerned, discussions spanning centuries have explored how human acts can be systematically classified in terms of their underlying ethical value to gauge their degree of goodness or badness. The most mature version, which consisted of five categories, beagn to take its full shape around the eleventh century (Baghdādī, 1977, pp. 337–338; Baṣrī, vol. 19831, pp. 4–5, 334–341). Since then, this fivefold classification has been consensually adopted and has remained mainstream, undergoing no major changes up to the present day (Faruki, 1966; Zankī, 2003).

The differences between the abovementioned secular threefold or fourfold scheme (viz, obligatory, prohibited, permissible, and supererogatory) and the fivefold classification in the Islamic tradition extend beyond just the number of categories or their names. They encompass other substantial aspects, including the very foundation of the classification and the essence of the respective categories.

This fivefold classification is referred to in Arabic by the term of al-aḥkām al-khamsa, which literally means “the five rulings”, and is usually translated into English as “five values”, “five categories” or “five principles” (Faruki, 1966; Firmage et al., 1990, p. 204, Kamali, 2003, p. 413). Given the nuanced perspectives presented in authoritative sources and the specific focus of this study, the fivefold classification of human acts is to be understood and approached through the following parameters.

The foundation of this classification rests on specific theological premises, as outlined in the previous section. Central to these premises is the conviction that the authority to determine what is good and bad fundamentally resides in the Creator of humans, the universe and all creatures therein—namely, God. Within this theological framework, the fivefold classification serves as a practical instrument to help those who believe in God and are convinced that His perfect divine attributes make Him the supreme Lawgiver and Arbitrator, capable of instructing humans on how to conduct themselves in a morally responsible manner. Consequently, both the individual posing the question about behavior in a specific scenario, known as the questioner (mustaftī), and the religious scholar acting as the religious advisor (muftī), who classifies the questioner's action into one of the five categories, share a common objective: aligning one's behavior with God’s will. In essence, the goal is to manifest sincere obedience to God and submission to His will (imtithāl), as opposed to catering to personal desires and preferences (hawā) (Baṣrī, 1983, vol. 2, pp. 211, 242; Faruki, 1966, p. 43; Juwaynī, 1996, vol. 1, pp. 160–171).

Within the context of the human-God relationship, adherence to this value system is primarily overseen by one’s conscience. If one’s behavior betrays any of the requirements ensuing from this system, the main cost here will be one’s moral failure in front of God. Therefore, both the transgression itself and the endeavor to rectify it initially fall within the private sphere of one’s relationship with God, both in the present life and, more significantly, in the Hereafter, where individuals will be held accountable before God (Faruki, 1966, p. 77, p. 91; Shafiʿī, 1940, p. 353;). This domain of individual morality constitutes the central focus of this study.

Moreover, actions that extend beyond the individual and impact others, with societal repercussions, can be subject to regulation by legislative and enforcement bodies. These entities aim to safeguard the rights of individuals and maintain public order in society. For instance, in the context of (non-) disclosure of incidental findings (IFs), hospitals or health ministries can operationalize the, legally speaking, non-binding value system into institutional policies or enforceable laws. While the legal dimension is not the primary focus of this study, the analyses provided can serve as a resource for institutions seeking to develop regulatory frameworks that align with this value system.

The concluding observation here aims to problematize the assumption held by some bioethicists that religious deliberations would necessarily yield positions “based on faith not argument.” This perception has sometimes led to the view that religious normativity stands apart from, or is even in opposition to, philosophical discourse (Blumenthal-Barby et al., 2022, p. 17; Savulescu, 2015, p. 32). The definitions provided below for each of the five categories have been meticulously drafted to highlight the moral dimensions inherent in the overall scheme and emphasize the necessity of supporting the resultant judgments with moral reasoning. This aligns with the mainstream approach adopted by both classical Muslim scholars and their contemporary counterparts. They consistently reiterate the need for prdudence and cautiousness before claiming that a specific position represents the ruling of God (ḥukm Allāh). Especially when it comes to the novel issues that fall within the scope of ijtihād, of which the management of IFs is a perfect example, human acts undergo evaluation to judge their ethical or unethical character (Baṣrī, 1983, vol. 1, pp. 8–9; Zankī, 2003, p. 336). To minimize the scope of error and or fallible subjectivity, scholars’ judgments are to be premised on consistent and robust religio-ethical reasoning. On the other hand, Muslim scholars have always been reluctant to hastily claim someone’s entitlement to divine reward or punishment, recognizing that such judgment primarily rests with God and that humans should not attempt to arrogate to themselves such authority (Abū Yūsuf, 1938, pp. 72–73; Faruki, 1966, pp. 68–79).

Against the backdrop of these parameters, the five categories are defined as follows:

  1. (a)

    Prohibited: An act deemed blameworthy when committed by someone who is recognized religiously as an accountable agent (mukallaf), as per the guidance of the Lawgiver, namely God.

  2. (b)

    Obligatory: An act whose commission by a mukallaf is praiseworthy, and its omission is considered blameworthy, as per the guidance of the Lawgiver.

  3. (c)

    Reprehensible: An act discouraged by the Lawgiver without being explicitly prohibited, making its commission not blameworthy.

  4. (d)

    Recommended: An act considered praiseworthy but not mandated by the Lawgiver; thus, its omission is not blameworthy.

  5. (e)

    Permissible: An act where commission or omission doesn’t entitle the mukallaf to either praise (madḥ/thanāʾ) or blame (dham/lawm). This is because the Lawgiver’s directives either don’t support its classification into any of the four aforementioned categories or do indicate that the act is morally neutral (Baṣrī, vol. 19831, pp. 334–341; Ibn al-ʿArabī, 1999, pp. 21–24; Ibn Qudāma, 2002, vol. 1, pp. 97–151; Sarakhsī, n.d., vol. 1, pp. 110–128; Shīrāzī, 2003, pp. 6–7, 12–25; Zankī, 2003, pp. 336–338).

Applied Case: Incidental Findings (IFs)

This study will utilize the fivefold categorization of human acts to classify the (non-) disclosure of specific Incidental Findings (IFs). Grounded in the above-outlined frames of metaethics and normative ethics, this fivefold categorization is considered the most fitting tool for an ethical management of IFs, enabling the classification of human acts on the basis of their moral worth. Rooted in the Islamic tradition, this multi-layered ethical analysis also aligns with aspects of secular moral discourses. We posit that constructing Sharia-based perspectives on complex issues, such as the ethical management of IFs, should always involve employing such a comprehensive approach.

This approach gains additional relevance considering the dynamic nature of genomics. The decreasing cost of sequencing, coupled with enhanced bioinformatics capabilities, has made genomic sequencing commonplace in both research and clinical settings. Genomic research routinely produces vast datasets, elevating the probability of encountering IFs unrelated to primary research goals. Moreover, exome and genome sequencing are swiftly being integrated into clinical practices for diverse medical applications, including molecular characterization of rare diseases, personalized treatment, pharmacogenomics, preconception/prenatal screening, and population screening for disease risk. In each of these scenarios, the likelihood of recognizing and reporting IFs with medical significance to the ordering physician and the patient is escalating (Green et al., 2013; Noohi & Ross, 2022). Given these advancements, the ethical management of IFs has become substantially more intricate, rendering a one-size-fits-all approach impractical.

The two categories, namely (a) obligatory and (b) prohibited, will be presented first. Both categories offer distinct and categorical judgments, facilitating straightforward decision-making without significant complexity or nuances. That is why many of the cases that fall within these categories can be incorporated into broad policies and guidelines for research and healthcare institutions. Examples, which will be discussed in detail below, comprise scenarios where the disclosure of life-saving IFs is considered obligatory, while revealing nonpaternity IFs to the presumed father is prohibited.

The other two categories, (c) recommended and (d) reprehensible, share affinities with the obligatory and prohibited categories, respectively. Acts not strictly deemed obligatory may shift to the less stringent category of recommended actions, and similarly, the relationship between reprehensible and forbidden acts follows a similar pattern. However, cases falling under the recommended and reprehensible categories often resist categorical judgments, subject to contextual and variable factors. As a result, these cases are better assessed on a case-by-case basis, ideally through referral to ethics committees. This approach captures the morally relevant nuances, as opposed to integrating them into generalized institutional policies.

The category of “permissible” typically encompasses IFs whose disclosure doesn’t align with any of the acts falling under the other four categories. Consequently, there won’t be a dedicated section for IFs in this category, given their nature of not fitting into the more defined ethical classifications.

It is important to note that the examples provided under each category are not meant to create an exhaustive list of what should or should not be disclosed. Instead, they serve as illustrative instances or representative examples, and many similar cases could already fit into these categories or become eligible for inclusion in the near or distant future. Moreover, it is crucial to acknowledge that classifying specific examples into these categories is dependent on the information available at the time of writing this study in Summer 2023. Updates to the currently available information can result in a shift in the categorization of particular findings.

Thus, it is crucial to realize that this dynamic categorization, particularly in judging the (non-) disclosure of specific findings, is closely linked to the continuous and rapid advancements in genetics and genomics, and cognate fields. Some researchers distinguish between individuals’ genetic “information,” which remains relatively static, and the “results” of genetic tests, the interpretation of which may change in response to advances in these fields (Roberts & Foulkes, 2020). Consequently, the American College of Medical Genetics and Genomics (ACMG) consistently updates their recommendations on which IFs should be disclosed, with the latest revisions released in 2022. These updates aim to accommodate the evolving medical value of certain genetic variants due to new discoveries in these fields (Kalia et al., 2017; Miller et al., 2021a, 2021b, 2022). An illustrative example showcasing the fluidity of the ACMG list is the TTR (transthyretin) gene. It was initially excluded, but was later included based on new data on population prevalence and FDA-approved treatments, indicating links with treatable causes of heart failure (Miller et al., 2022, 1408).