Renegotiation, uncertainty, imagination: Assemblage perspectives on reproductive and family planning with an Inborn Error of immunity

Abstract

Advances within the new genetics expand our understanding of the scope and presentation of inherited conditions, particularly to include incompletely penetrant and variably expressive conditions. These features can complicate patients’ reproductive and family planning processes, in part because they expand the possibilities of life with an inherited condition. Despite many inquiries into reproductive planning with an inherited condition, accounts of experiential knowledge and reproductive planning fail to adequately describe the uncertainties experienced by people living with incompletely penetrant and variably expressive conditions. To address this gap, we conducted a qualitative, cross-sectional study using assemblage theory to characterize the impacts of experiential knowledge on reproductive planning for individuals living with Inborn Errors of Immunity (IEI) that exhibit incomplete penetrance and variable expressivity.

Eligible participants were between ages 18 and 48, with a diagnosis of either GATA2 deficiency, PIK3CD gain-of-function disorder, or CTLA4 deficiency. Using an abductive thematic approach, attention was paid to the people, ideas, and non-human objects embedded within participants’ accounts of disease experience and reproductive planning. Organized around the objects of genetic diagnosis, the body, and hypothetical children, this analysis illustrates how disease can be conceptualized as an assemblage of human and non-human objects which provoke numerous actions and affective engagements in reproductive planning. These engagements include renegotiation, uncertainty, and imagination. By emphasizing the distribution of agency and action across systems, processes, and relationships, assemblage theory invites novel ways of understanding the role of experiential knowledge on reproductive planning.

1. Introduction

1.1. Reproductive planning in incompletely penetrant and variably expressive disease

Over the last few decades, questions of reproductive and family planning with a known inherited disease risk have been closely examined within the medical social sciences. Among many insights from this work, reproductive planning with a known disease risk is understood to be emotionally and decisionally overwhelming (Hughes et al., 2021; Pastore et al., 2019). This overwhelm is exacerbated by the growing options of prenatal and preconception genetic testing currently available. These technologies, which underscore what Marcia Inhorn calls a contemporary “quest for conception”, have brought reproductive life and its associated decisions into the fold of highly technological, moral, and temporal engagements (Inhorn, 2020).

Importantly, genetic testing only reveals the presence of disease-causing genetic variants—not the severity of the disease or the symptoms that will manifest. This is a critical caveat for the prenatal detection of incompletely penetrant and variably expressive conditions. Incomplete penetrance refers to the potential for presence or absence of a condition when carrying an associated disease-causing genetic variant. Variable expressivity refers to the ability of a disease to present with a range of different clinical manifestations. Incompletely penetrant and variably expressive conditions are increasingly ascertained in clinical genetics follow-up, and thus able to be detected prenatally especially in the event of a family member being a known carrier. These features introduce added layers of complexity to living with a genetic condition by introducing the possibility that one might live with a disease-causing variant, but have any number of disease manifestations including no disease whatsoever. This expanded spectrum of disease possibility, and understanding what it might mean to live within this evolving spectrum, is one cornerstone of research examining the “new genetics”, a term coined by social science scholars to describe the various impacts of genetic advancement on human experience (Finkler et al., 2003).

Within reproductive planning literature, it has been suggested that individuals living with inherited disease draw on many distinct resources to make sense of their disease risk, ranging from embodied knowledge, to everyday experience, to the integration of broader cultural messages about the condition (Boardman, 2014). Early research in reproductive decision-making quickly found that closely living with and thus witnessing the experiences of affected relatives often concretized a sense of responsibility to prevent disease transmission (Downing, 2005; James et al., 2003; Kay and Kingston, 2002). Even the process of eliciting and disclosing family history—a core component of the clinical genetics encounter—itself holds the potential to prompt reconceptualization of risk within the family system (Arribas-Ayllon et al., 2011) or by one’s self (Dimond, 2014). Incompletely penetrant and variably expressive conditions may introduce additional uncertainty in reproductive planning (Hughes et al., 2021), due to the fact that these common resources of knowledge take on new and added forms to reflect the spectrum of disease.

Despite the breadth of this literature, there remains limited insight for individuals with incompletely penetrant conditions which vary in severity. Further, many accounts on reproductive and family planning with inherited disease explore the perspectives and decisions of unaffected individuals with a known inherited disease risk. These accounts largely examine common, highly penetrant recessive diseases like sickle cell anemia and cystic fibrosis (Kazmerski et al., 2022; Ranee and Skirton, 2019), many of which are characterized by participants’ motivation to reduce transmission of the inherited disease (Dommering et al., 2010; Myring et al., 2011; Ranee and Skirton, 2019). As a result, this narrative may not effectively capture the full scope of concerns or priorities of several groups of individuals living with genetic disease, including those with incompletely penetrant and variably expressive conditions.

1.2. Assemblage theory: an organizing concept

Recently, the term experiential knowledge has been used to encompass the broad embodied, relational, and societal resources involved in reproductive and family planning with an inherited disease (Boardman, 2014). Boardman’s conceptualization of experiential knowledge builds on a long history of research into patient experience, and incorporates different human and non-human objects, including persons, diseases, socio-cultural beliefs, and embodiment. Each of these attributes produce “multiple, distinct, and sometimes competing” lenses of experiential knowledge, which in turn inform reproductive decision-making (Boardman, 2017). Thus, an analytical approach which adequately attends to the complex relationships underscoring experiential knowledge expands the understanding of reproductive planning in inherited disease.

Assemblage theory is a philosophical approach concerned with the engagements between systems, processes, and relationships, including human actors and non-human entities. Originally characterized by Gilles Deleuze (Deleuze and Guattari, 1987), assemblage theory has been used across a number of social science topics, including sociology of mental illness and recovery (Price-Robertson et al., 2017), consumption (Epp and Amber, 2015), and international health (Chenhall and Senior, 2018). Using Deleuze’s framing, tangible objects like genes, affects, signs and symbols, or social movements can enact as powerful an influence on a given phenomenon as human actors. Importantly, assemblage theory understands these objects as dynamic, agentive, and embedded in constantly-evolving relationships (Neely, 2023). Examining these relationships and their influences can illuminate meaning about broader phenomena. For example, Duff’s (2014) exploration of the assemblage of drug use presents several important objects of the drug use assemblage: the user’s environment, the body, and drug-induced affect. Duff argues that each of these objects engage with drug use in ways that render them not only meaningful in themselves, but insightful about the drug use process. Critically, these non-human insights have impacts on the human actors—in Duff’s case, individuals using illicit drugs—within the assemblage.

1.3. Inborn Errors of Immunity: A complex reprogenetic Frontier

With advancements in genomic medicine, several dozen novel Inborn Errors of Immunity (IEIs) have been discovered, with approximately 500 genes causative of an IEI currently identified (Castagnoli et al., 2019). Comprehensive genetic testing has now become an integral part of the identification and care of individuals presenting with an IEI phenotype (Karimi et al., 2021). Once known as primary immunodeficiencies, IEIs demonstrate incomplete penetrance and can present with a broad constellation of symptoms, including immunodeficiency, atypical infection, autoimmunity, skin findings, lymphedema, inflammation, atopy, and/or malignancy (Bousfiha et al., 2017). In this analysis, three autosomal dominant, variably expressive and incompletely penetrant IEIs were selected: GATA2 deficiency, CTLA4 deficiency, and PIK3CD gain-of-function disorder. GATA2 deficiency is characterized by myelodysplastic syndrome, lung disease, and complications of the lymphatic and vascular systems. CTLA4 Deficiency is characterized by intestinal disease, autoimmune complications, hepatosplenomegaly and lymphatic and vascular system anomalies. PIK3CD gain-of-function disorder, also known as PASLI, is characterized by susceptibility to respiratory and bacterial infection as well as a risk of lymphoma.

With the introduction of intravenous immunoglobulin replacement therapy in the 1980s, mortality for many IEIs has decreased over time while quality of life has substantially increased (Eddens et al., 2022). Living an independent life, which can include life milestones like parenthood (Gennery and Lankester, 2019), is now possible with an IEI—and in the case of individuals found to have an IEI with no symptom presentation, has been possible in the past yet newly reconceptualized. For symptomatic individuals, however, this possibility also introduces new complications. Although several case studies indicate that pregnancy can be well-tolerated in patients with IEI (Borte et al., 2022; Laakso et al., 2022), careful management by interdisciplinary care teams is still presently recommended (Sheikhbahaei et al., 2018).

An important barrier to family planning for patients with IEI is caused by the conditioning involved with hematopoietic stem cell transplant (HSCT), an increasingly common treatment strategy for IEIs (Castagnoli et al., 2019) that reduces fertility (Nabhan et al., 2010). Fertility preservation is possible prior to HSCT and includes procedures for egg and sperm retrieval (Hoffman et al., 2021). However, accessibility of fertility preservation strategies and subsequent in-vitro fertilization (IVF) may be constrained by the cost and availability of services (Flink et al., 2017; Hoffman et al., 2021). Prior work exploring the experience of young adult women undergoing HSCT for hematological malignancy has highlighted the liminal experience of undergoing HSCT, including considerations regarding one’s future reproductive plans (Halliday et al., 2015). While this work might lend some insight into the experiences of IEI patients, the varied disease presentation and implications for offspring from IEI may not be as appreciated in accounts from patients living with hematologic malignancy.

To date, there has been one study published exploring pregnancy beliefs and outcomes among women with IEI. Exploring these questions in women with Chronic Variable Immunodeficiency and Hypogammaglobulinemia via online survey, this work found that over half of respondents felt that their condition affected their reproductive decision-making process (Gundlapalli et al., 2015). This limited research suggests this is a topic of concern to patients with IEI. While variable expressivity and reduced penetrance add another layer of complexity to risk appraisal, presently little is known about how the IEI population appraises their risk of passing on their condition to their offspring given these complex inheritance features.

Taken together, existing research highlights several complex demands on patients with IEI in reproductive planning which deserve further exploration. Using assemblage theory, this analysis explored experiential knowledge in relation to reproductive planning for patients with IEI. By understanding experiential knowledge through its fluid dynamics and evolving relationships between objects, relationships, and ideas, assemblage theory invites novel ways of understanding reproductive planning.

2. Methods

2.1. Procedures

This study was reviewed and approved by the Johns Hopkins IRB. Participants were recruited through an existing protocol at the National Institutes of Allergy and Infectious Disease aimed at characterizing inherited immune syndromes (Protocol number NCT03206099). Individuals were eligible to participate based on two criteria: first, they had a confirmed molecular diagnosis of GATA2 deficiency, CTLA4 deficiency, or PIK3CD gain-of-function disorder. Second, we recruited broadly on the basis of age (ages 18 to 48) to account for the increasing trend of delayed parenthood, also known as the “postponement transition” (Kohler et al., 2002).

Participant demographic and diagnostic information collected for protocol NCT03206099 were reviewed by the first and fourth author (the PI of the existing protocol) to identify potentially eligible participants. Individuals who provided prior consent to be contacted for future research studies and preliminarily met eligibility criteria were sent an email with a brief description of the study, along with a link to a screening survey (Appendix 1). The purpose of the screening survey was two-fold: first, to assess eligibility for participation; second, to build a maximum variation sample based on sociodemographic features, illness severity, and reproductive preferences. Maximum variation sampling affords the opportunity to ascertain themes which may cut across varied indices of participant identity and experience (Patton, 2002). Given limited research on lived experience of individuals with IEIs, and the deeply varied and personal nature of reproductive planning with an inherited disease, our goal was to build a diverse sample. Using the concept of information power described by Malterud et al. (2016), we aimed for a final sample of 20–25 interviews.

Interviews were completed by the first author, who was at the time a genetic counseling graduate student, and recorded over Zoom between March 2023 and July 2023, and later transcribed by an outside transcription service (Production Transcripts). Verbal consent was obtained before the interviews. Once consented, the interview began with a personal introduction from the interviewer, including their personal and research background as well as purpose and interest in the research question. Interview domains and related questions in the interview guide can be seen in Appendix 2.

2.2. Positionality

This project and its analysis were executed by all members of the authorship team, all of which are female. Several members of the authorship team work as, or were in training to be, genetic counselors at the time of writing this paper. Two of these genetic counselors had close working experiences within the IEI community through the existing protocol, which included previously consenting several of the participants to whole-genome sequencing. Two members of the team are social scientists with expertise in anthropology and sociology of health and medicine. Across the team, diverse understandings of what constitutes family were evident and informed the development of study instruments as well as the analysis of interviews.

2.3. Analysis

Analysis of interview data followed an abductive approach (Tavory and Timmermans, 2014). Abduction moves between theoretical knowledge and empirical evidence to bring together and critically interrogate previously unrelated ideas to “discern novel patterns, connections, loops, and relationships both within the existing data, through time, and across wider pools of evidence and theory” (Neale, 2021, p. 270). Integral to this approach is maintaining a consistent conversation between one’s data and theoretical perspectives (Tavory and Timmermans, 2014). This relationship was crafted in many ways, including through reflective notes written immediately after interviews, to reading and re-reading transcripts over the course of the analysis, making annotations for interesting or unexpected insights, and writing detailed memos about participants. From these actions, an initial codebook was devised from the primary author’s engagement of two initial transcripts. This codebook was regularly updated over the course of the project and spanned codes detailing experience with condition and condition beliefs, personal understanding of complex inheritance features, genetic diagnosis, care experiences and needs, family relationships, and finally reproductive intentions and related attitudes. All analysis, including coding, memos, and notetaking were completed in MaxQDA (2018). https://www.icpsr.umich.edu/

As engagement with the data continued, it became evident that reproductive planning for individuals with IEI intersected not only with many different facets of one’s condition, but also their personal, medical, and family lives. Assemblage theory, with its focus on rhizomic connections between the numerous objects which make up a social process, appeared to be a compelling frame to account for this complexity. The first author began to review the transcripts, memos, and generated codebook with the aim of understanding the relationships between objects found within accounts of disease experience and reproductive planning. This meant that attention was paid to the people, ideas, and non-human objects which arose commonly within participants’ accounts, such as specific family members, scientific objects (e.g., genes) and encounters (e.g., provider interactions). Our analysis focused on understanding how these objects were embedded within webs of people, processes, and phenomena related to disease experience and reproductive planning. Results were reviewed by the remaining members of the research team through continual discussion during manuscript generation. Due to constraints of training timelines, the findings of this work were not member-checked or returned to participants.

3. Results

A list of interview participants can be found in Table 1. Of 41 eligible individuals from the existing protocol, 24 individuals responded to the screening survey. One individual did not respond to follow-up for scheduling an interview. In total, 23 interviews were completed with individuals ranging in age from 18 to 48 (mean age 32 years). The average length of interview was 60 min, ranging from 25 min in length to 2 h. One interview involved two participants: a husband with GATA2 deficiency and his wife who was unaffected, but underwent IVF with PGD to prevent transmission of the GATA2 familial variant. Participants represented a range of reproductive planning preferences. Some participants were parents (N = 7, 30%), some were actively considering parenthood (N = 5, 22%) or considering it as a future priority (N = 5, 22%), or uncertain of whether they wanted children (N = 2, 9%), and some had considered building a family, but were no longer considering the prospect at this time (N = 4, 17%).

Table 1.

Overview of participants.

Participant Name	Condition	Gender	Age Range	General Health Status	Family Planning Goals or Status
Laura	GATA2 Deficiency	Female	18-28	Fair	No longer considering building a family.
Avery	GATA2 Deficiency	Nonbinary	40–48	Good	Actively considering building a family
Heather	PIK3CD Gain-of-function	Female	40-48	Good	Parent
Allyson	PIK3CD Gain-of-function	Female	29–39	Good	Actively considering building a family
Eric	PIK3CD Gain-of-function	Male	29–39	Good	Not presently considering building a family but may consider someday
Shante	GATA2 Deficiency	Female	29–39	Good	Not presently considering building a family but may consider someday
Ella	CTLA4 Deficiency	Female	29-39	Fair	No longer considering building a family
Lia	GATA2 Deficiency	Female	18–28	Very good	Not presently considering building a family but may consider someday
Jared	PIK3CD Gain-of-function	Male	18–28	Very good	Not presently considering building a family but may consider someday
Robert	PIK3CD Gain-of-function	Male	18–28	Good	Not presently considering building a family but may consider someday
Kelvin	GATA2 Deficiency	Male	18–28	Good	Unsure
Phillip	PIK3CD Gain-of-function disorder	Male	18-28	Good	Unsure
Terren (and wife)a	GATA2 Deficiency	Male	29-39	Excellent	Parent
Nora	GATA2 Deficiency	Female	40–48	Very good	No longer considering building a family
John	GATA2 Deficiency	Male	40–48	Fair	Parent
Katie	GATA2 Deficiency	Female	40–48	Very good	No longer considering building a family
Reba	GATA2 Deficiency	Female	40-48	Good	Parent
Janet	GATA2 Deficiency	Female	29-39	Fair	Actively considering building a family
Evie	GATA2 Deficiency	Female	40–48	Fair	Parent
Christopher	GATA2 Deficiency	Male	40-48	Very good	Parent
Charlotte	GATA2 Deficiency	Female	18-28	Good	Actively considering building a family
Olivia	GATA2 Deficiency	Female	18-28	Excellent	Parent
Megan	GATA2 Deficiency	Female	18-28	Good	Actively considering building a family

^aOne participant with GATA2 deficiency requested to complete the interview with his spouse because she had undergone the IVF procedures discussed heavily in their interview.

The results are organized around three objects critical to participants’ reproductive and family planning considerations: genetic diagnosis, the body, and hypothetical children. Specifically, we describe below how these objects, and their web of relations invite new understandings of how people think about families, the role of experiential knowledge, and reproductive and family planning with an IEI. All names below are pseudonyms.

3.1. Genetic diagnosis

A confirmed genetic diagnosis of IEI prompted participants to reexamine their understanding of their disease. Participants reconsidered how IEIs were passed down in their family, who was and was not affected, what family history might be attributable to the diagnosis, and reproductive plans.

Several participants were a part of families with multiple, diagnosed relatives. These participants drew new connections between family members, informed by the knowledge revealed from their diagnosis. Often, these participants understood their condition in part through the constellation of symptoms shared between themselves and other relatives, including the possibility that the IEI could present differently between them and their family members. In these cases, receiving a diagnosis was unsurprising and reinforced dominant family narratives about the transmission or existence of disease. Evie, a participant who lived with GATA2 deficiency symptoms for most of her life, understood her tendency to get sick more frequently and severely in the context of a family network with variable presentation of disease well before receiving her own molecular diagnosis.

I knew that my family was sick and they all had the GATA2 mutation. And we all had different kinds of GATA2. And then I was 27, and I got to hear from my doctor that I had the GATA2 like my family, but that in a different way because my cousin, she was 16 and she got leukemia and I have a nephew who got lymphedema and leukemia.

(Evie, Female, 40–48, GATA2 Deficiency, Post-HSCT, Mother of 2)

Ultimately, Evie’s experience of receiving a diagnosis was contextualized by the pre-existing symptoms, signs, and health histories of her affected family members. For other participants, receiving their own genetic diagnosis prompted subsequent familial testing. In several of these cases, familial genetic testing diagnosed asymptomatic relatives with the same IEI as the affected individual. These experiences reconfigured relationships around disease and sometimes invited participants to reassess the transmission of their disease through their family:

My parents immediately did genetic testing. So did my sister. My sister does not have it. My dad does, and my mom does not … [in] my dad’s family there is one part of the family … Out of his mom and uncle, there were two others that passed away in their early twenties, and his grandmother had a twin sister who also passed away when she was 14, so we think the link is from … this part of my dad’s family.

(Katie, Female, 40–48, GATA2 Deficiency, Post-HSCT, No longer considering having children)

Following genetic diagnosis—and her family’s genetic testing—Katie and her father were no longer the unaffected parent and affected child. Instead, they shared a connection that Katie theorized to include various members of her father’s extended family. Genetic diagnosis prompted Katie and other participants to speculate about the transmission of their condition through prior generations of their family.

These new understandings of family ties factored in to reproductive and family planning. Similar disease presentation among relatives provided insight into management or manifestation of IEI symptoms for subsequent generations. Family experience of disease also informed family planning strategies. Terren was diagnosed with GATA2 deficiency after his father’s sudden passing from a condition-related infection but was asymptomatic at the time of the interview. He and his wife promptly sought information on how to prevent having a child with GATA2 deficiency shortly after his diagnosis:

Pretty much right after that, we were, like, having to jump back in to, “We got to figure this out.” … We found out that they could do, like, genetic PGD, pre-implantation genetic diagnosis, and there was no probe that had been created yet for GATA2 … There was not even, like, there wasn’t even a glimmer of hope that insurance was going to cover any of this, even though we were like, “His dad died from this. There’s family members who have died from this … [Pursuing IVF with PGD] would be preventative.”

(Wife of Terren, 29–39, GATA2 Deficiency, Pre-HSCT, Parents to 2 children)

Terren and his wife acted on GATA2 deficiency as a health threat to subsequent generations based on his father’s experience with and passing from the condition. Importantly, the motivation to utilize IVF with PGD for the familial GATA2 variant was significant enough that Terren and his wife were willing to overcome significant technological and financial barriers.

While diagnosis afforded some participants a clear path of action in reproductive planning, it introduced uncertainty into reproductive plans for others. For these participants, a shared diagnosis within the family tree offered an incomplete, and often uncertain, understanding of what it meant to pass on an IEI. Heather, a mother, experienced liver failure when she was 16, before she or anyone else in her family received a genetic diagnosis of PIK3CD Gain-of-function disorder. During her interview, she spoke often of how she traced the family’s symptoms through different family members, and the speculation this invited about her own chances of having transmitted the condition. In the ensuing years, she, her mother and brother, and her children would receive a genetic diagnosis of PIK3CD gain-of-function disorder. The question of whether or not she should have had her children—now knowing in hindsight her genetic diagnosis, and later, theirs—were central to her interview.:

[E]very time we’d go to a doctor, it would be “Well, do you think this is related?” and you’d hear ‘Oh, well, maybe.’ ‘Oh, I don’t think so,’ and then you’d get other doctors who are like ‘Yeah, I’m 100% sure it’s related,’ and now, they’re pretty well sure it’s related. So, when we got this [PIK3CD GOF disorder] diagnosis … It started terrifying me because none of [my brother’s] symptoms were the same as my symptoms. So, I was wonder[ing] if it was related to the mutation and it made me fear for my kids.

(Heather, Female, 40-48, PIK3CD gain-of-function disorder, no HSCT, mother of 4 children)

Heather’s genetic diagnosis provided insight into the spectrum of her condition that was directly reflected by her brother’s disease experience. Together, her diagnosis and the contrasting experiences between her and her brother introduced uncertainty about how this diagnosis will impact her children. Taken together, these experiences suggest that genetic diagnosis does more than provide a disease etiology: it invites the person receiving the diagnosis to reconceptualize family ties, to reconsider prognostic expectations, and to reassess reproductive plans.

3.2. The body

While genetic diagnosis provides one thread of insight into participants’ conditions, the body is also a tool from which participants derive insight over time. Participants spoke about their bodies in terms of symptoms and signs, while HCST prompted consideration of the body’s constitutive parts. Both symptomatic and asymptomatic participants described ways of understanding their bodies as sites of knowledge accumulation. Symptomatic participants understood themselves as different from healthy friends and family through the symptoms that manifested in their body. For asymptomatic participants, knowledge stemmed from symptom surveillance, including annual bloodwork or bone marrow biopsy. Surveillance reorganized some participants’ lives around the body and monitoring for emergent symptoms.

It’s … a little bit anxiety-inducing because you don’t know [if you will develop symptoms] at this point. Like, at first it was like no big deal, because … my counts were all really good still. And now they’re sort of like medium to bad, but I feel fine … It’s like any year it could be the year where they’re like, “It’s go time” … So it is a weird sort of cadence to my life of like, I don’t feel like I can like, plan more than 12 months in advance.

(Lia, Female, 18–28, GATA2 Deficiency, pre-HSCT, Not presently considering having children, but may have children someday)

Many participants were aware of their condition’s varied severity. They recognized that their disease experience represented one of many possible experiences within their diagnosis. This awareness complicated many participants’ ability to rely on embodied experiential knowledge in reproductive and family planning.

If my kid had to go through the same thing that I went through I would not choose to have kids if I knew that. That’s just definitely something that I know of now looking back. But if I can have kids and they can go through it—you know, if they get GATA2, and their treatment was easier or definitely not as painful as mine, then it would be something that I would still consider. But I guess it’s just too early to tell.

(Kelvin, Male, 18–28, GATA2 Deficiency, Post-HSCT, Unsure about having children)

Complex conversations between the body, its products, and reproductive planning also emerged from participants’ experiences undergoing HSCT. Although HSCT increased most participants’ quality of life by reducing symptoms and disease severity, this improvement was not without costs. Several participants used fertility preservation out of concern for reduced fertility associated with HSCT. This procedure necessitated prolonged and often complex engagement with products of the body: germ cells (sperm and ova) and related tissues. In early adolescence, Kelvin cryopreserved testicular tissue prior to his HSCT in the hopes of generating sperm from this tissue for future use. Years later, questions about the usability of this tissue remain:

[W]e’re waiting now technically for the science to be developed later to make those cells usable … Two years ago I tried seeing if the specimens that they collected actually contained usable cells, and so they will not actually test that because if they test it and then find that there are no usable material with today’s science, those specimens must be destroyed … And so I just went ahead with let’s not test it, let’s not even know, we’ll keep it on ice until later.

(Kelvin, Male 18–28, GATA2 Deficiency, Post-HSCT, Unsure about having children)

For Kelvin, engagements with the products of his body invite as much, if not more, doubt as engaging with the body itself. Other participants who underwent fertility preservation experienced similar kinds of doubt when engaging the products of their bodies. This included many questions about what comes after the fertility preservation process, such as whether to do pre-implantation genetic testing, IVF failure risks, or what to do with unused embryos. Additionally, two participants in our sample conceived children post-HSCT. For both participants, these pregnancies evoked questions about both the products of their body and the capacities of their post-transplant body.

I said, “I was at the hospital that in 2016 and ’17, they told me it was all destroyed because of the radiation and the chemotherapy.” And they said, “We have no explanation for that.” He thought it was all destroyed. They have checked it many times and they said, “You can’t have children.” And now my eggs are back. I have normal eggs … So I don’t know what’s going on in my body.

(Evie, Female, 40–48, GATA2 Deficiency, Post-HSCT, Mother of 2)

Questions like Evie’s illustrate how technology itself does not afford certainty or clarity. Instead, it often introduced new and unexpected questions related to reproductive planning which individuals must contend with over time. As a result, the body—when understood through its symptoms, monitoring, and prolonged engagement with its products—provides a conduit for evolving complexities of decision-making with an IEI.

3.3. Hypothetical children

Participants reconciled conflicts between experiential knowledge and their reproductive hopes and preferences through considering “hypothetical children.” Participants conceptualized hypothetical children in relation to their own experiences, including improved management for their condition. Medical progress inspired hope for some participants around their capacity to parent a child living with an IEI. This use of the hypothetical child underscored beliefs about ongoing improvement of treatments.

I knew there was a chance but with the progression that I’ve seen or experienced with the medical world, it’s like, "Okay, so well, they—I could teach them how to handle certain situations with my life experience." So, I try to look at things positively.

(Allyson, Female, 40–48, PIK3CD Gain-of-Function disorder, No transplant, Presently considering having children)

When undergoing fertility preservation, participants were not always certain whether they wished to build a family in the future. For these participants, fertility preservation invited them to imagine and consider a life with future, hypothetical children.

I’m doing this process to potentially, you know, create a life in the future … It kind of opened my eyes, I guess, to be, you know, a little bit more grateful about … my situation because it could be worse. And then just going through the motions of, okay, well, do I really want to have kids? Is this something that, you know, just going back and forth emotionally about, you known, the decision.

(Shante, Female, 29–39, GATA2 deficiency, post-transplant, Not presently considering having children but may consider someday)

In the process of considering the use of IVF with PGD, participants held both the promise and uncertainty of technology to produce hypothetical children. While undergoing IVF, Terren and his wife faced ongoing questions about the possibility and reliability of a PGD test for GATA2 deficiency:

But if we knew that there was an opportunity for us to prevent that for our children, we were going to go to the ends of the earth to do it. But when it was like up in the air whether or not that probe could be created, and it was kind of like we were told this might not work out at all, it was like, okay, well, then we at least know we got to this point and did everything we could. And then that I think would have been easier for us to accept that we could just have children naturally and accept the outcome whatever it was. But I don’t know if we could have forgiven ourselves if we hadn’t tried everything.

(Terren, Male, 29–39, GATA2 Deficiency, asymptomatic pre-HSCT, parent of two daughters through IVF with PGD)

Terren and his wife weathered the uncertain nature of this technology by considering its possible impacts on their hypothetical children. For them, a chance for their children to avoid living with GATA2 deficiency was worth the limitations accompanying IVF and PGT.

Hypothetical children also served as a resource in reproductive planning outside of the use of reproductive technologies. For participants who decided not to have children, hypothetical children were the mechanism through which they weighed parenting hopes and beliefs, living with their condition, and the physical demands of parenting.

[A]s things went on, aplastic [anemia] was hard to get through, but since then I have had other things that are much more difficult to get through, and so it became easier to accept that I have limits, and a lot of that comes with maturity too and just life experience … it’s like, “Okay. I have a hard time even sustaining me.” Put a child on top of that and then just, you know, there are some times it’s like I have to have a cane to get around. Like I don’t have the energy to walk around with a kid or go find them and things like that.

(Ella, Female, 29–39, CTLA4 deficiency, No transplant, No longer considering having children)

Other participants considered their personal capacities given their condition and the impact these capacities might have on hypothetical children. Some participants felt their future health was too inherently uncertain to justify having children, even when parenting was desirable. Laura described a harrowing experience with GATA2 deficiency, and still experiences symptoms following her HSCT. In her interview, she discussed the difficult decision to forego having children:

[W]hat if I have a child and then ovarian cancer tries to kill me in a couple years? That might sound selfish, but I wanted children, but I wasn’t going to … sacrifice me to put a child on this Earth … I feel like I made the right decision, but I just thought there was more people that needed me than me and my husband needing a child.

(Laura, Female, 29–39, GATA2 deficiency, Post-HSCT, No longer considering having children)

For Ella and Laura, hypothetical children provided a thought space for negotiating their feelings about parenthood. Within this thought space, they each weighed the complex and ongoing aspects of their condition with conflicting feelings surrounding reproductive decisions. For them, and others, hypothetical children emerge in spaces of discernment between the experiences and beliefs around one’s condition, hopes for the future, and capacities of the body.

4. Discussion

This analysis explored how experiential knowledge comes to bear on reproductive planning for a subset of individuals living with an IEI. Although our work suggests that that these diagnostic features do indeed complicate the appraisal and meaning applied to one’s condition in reproductive planning, it also illustrates how individuals draw on familiar objects (family, the body, and envisioned family) as part of the reproductive planning process. Our results demonstrated how disease experience, when conceptualized as an assemblage of human and non-human objects, provided insights into the highly personalized nature of reproductive planning while living with an IEI. These objects inspire renegotiation, uncertainty, and imagination in our participants’ experiences of reproductive planning.

Genetic testing is an emerging component of care for individuals living with an IEI (Karimi et al., 2021). Consequently, there is a limited understanding of how individuals living with IEI attach and derive meaning from their genetic diagnosis. Our work offers insight into the way that meaning is made about genetics for patients with IEI. First, patients living with an IEI have been living with an unfolding and evolving clinical and genetic portrait of their condition for some time. Although a confirmed genetic diagnosis may offer clarity, the incompletely penetrant and variably expressive nature of IEIs expanded the perceived spectrum of symptoms, severity, and therefore quality of life with an IEI. Genetic diagnoses had a significant impact on participants’ understandings of the incomplete penetrance and variable expressivity associated with conditions, especially when a genetic diagnosis elucidated who else in the family did and did not carry the variant. The genetic status (who has and does not have the variant) of family members, as well as the manifestation of symptoms in the self and relatives, thus factor in to individual sense-making of a genetic diagnosis.

Importantly, this altered conceptualization of the disease informed the perceived riskiness of disease inheritance. For some, this manifested as a reinforcement of the disease as something to avoid transmitting; for others, the risk became more ambiguous as the potential spectrum of severity expanded. This suggests that in the case of incompletely penetrant or variably expressive disease, the spectrum of risk appraisal in reproductive planning mirrors the spectrum of severity and presentation of the disease—with the self and surrounding family members as critical examples in which to anchor one’s understanding, fears, and hopes.

The body—when considered both as a whole and in its constituent parts—was another important, yet inherently uncertain, resource from which to draw in planning one’s reproductive future. This uncertainty is especially resonant in the engagements which arose between participants’ bodies and reproductive technologies. While intended to preserve the possibility of building a family, the reproductive technologies utilized by participants invited unanswerable questions surrounding technological feasibility, the reproductive capacity of their bodies, or affective dimensions of family planning. These cascading forms of uncertainty related to reproductive technologies are at odds with prevailing ideas about the promise and potential of ART, which has been historically presented as a “hope technology” (Franklin, 2022; Helosvuori, 2020) intended to help individuals overcome limitations to fertility set forth by the material body. Scholars in the sociology of ART have long complicated this message, acknowledging the paradoxical relationship between hope and uncertainty which emerges from utilizing ART (Franklin, 2022). Our participants’ accounts suggest that in the case of incompletely penetrant and variably expressive conditions, this paradox touches multiple inflection points within reproductive planning, from the vision of parenthood with an inherited disease, to weighing decisions to preserve germ tissue. It is imperative to consider these material and affective engagements alongside the technologies themselves.

One critical way that participants reconciled this uncertainty in reproductive planning was through the process of envisioning family, materialized through consideration of the “hypothetical child”. Engagements of hypothetical children revealed considerations of hope, possibility, and subsequent actions related to reproductive planning. As a result, the hypothetical child functioned as what Smith et al. (2023) calls a “thought space” for planning reproductive actions. Within this thought space, imagining a reproductive future is itself a complex resource that generates actions from individuals. One prominent action which took form was reconciliation of the needs and possibilities of hypothetical children with prior experience and future possibilities. Prior research on kinship, genetics, and reproduction has described the envisioning of future family formation as a resource to inform exploration of both affect and action regarding family planning (Clarke et al., 2020; Smith et al., 2023). For our participants, ideas about “hope” and “possibility” involved a reconciliation of prior ideas, existing objects, and reproductive futures. Reconciliation of these different objects informed a vast range of reproductive actions, including to forgo parenting entirely. From this reconciliation of objects, a vast range of reproductive actions, including the decision to forego parenting entirely, ensued.

Our participants frequently discussed considerations for reproductive planning that intersected with condition management, particularly HSCT and the tension of weighing disease prognosis and reproductive potential. The findings of this work may be relevant for several other inherited conditions where HSCT is indicated, including hemoglobin-opathies such as sickle cell disease and beta thalassemia, as well as those with an increased risk of hematologic malignancy like Li Fraumeni Syndrome. Exploration of the tensions between condition management and reproductive planning for other individuals pursuing HSCT due to an inherited condition is a rich area for further exploration.

As genetic medicine continues to expand, the meanings and logics which accompany common objects of genetic disease—for both medical and lay actors—will also grow. In his exploration of geneticization using the concept of assemblage, Arribas-Ayllon (2016) argues that now is the time to explore genetic medicine through the lens of assemblage theory. He presents the possibility that assemblage thinking in genetic medicine might replace static understandings with those which “recognizes the immanence of power relations, the self-organizing processes of networks that form new, often affirmative relations between persons, mutations, categories, explanations, [and] probabilities of risk” (138). Objects that may have previously held more static, or predictable, meanings in genetic medicine reveal themselves be dynamic and highly personalized resources for reconceptualizing patient experiences and subsequent actions. This challenges ideas of cause and effect that dominate positivistic research on human behavior and decision-making, instead suggesting that multiple possibilities and logics of living with an inherited disease can emerge from single inherited diseases or disease groups.

This work has several limitations. Participants were recruited from an existing research protocol at the National Institutes of Health and may not reflect the racial, ethnic, and class diversity of individuals living with an IEI. GATA2 deficiency is well-represented in our sample, which may limit the applicability of findings to all IEI patients. However, this work has several strengths, including that male participants are sampled in our interview at a higher frequency than in other reproductive decision-making research, which frequently centers female voices (James et al., 2003; Sawyer et al., 2005). Of note, one participant requested that we complete the interview including his wife, who underwent IVF. Our institutional IRB granted a one-time exemption to our protocol for this interviewee. The depth afforded by including partners is a valuable consideration for future qualitative interview studies on reproductive planning.

Assemblage theory elucidated the myriad ways that participants deployed experiential knowledge as a resource in reproductive planning. What flowed from these engagements are complex questions and considerations from participants about their reproductive plans that often have few tangible solutions. Our analysis calls attention to how the distinct features of IEI inspire novel trajectories for these common objects. As the new genetics continues to prompt expansion of genetics in care (Clarke et al., 2020), understanding the objects in contact with genetic medicine—and their emergent impacts and potentials in patients’ experiences—will provide valuable insight into meeting the demands and realizing the potentials of personalized genomic medicine.

Data availability

Study documents, including the interview guide, sampling survey, and coding queries related to the protocol, can be reviewed upon request on ICPSR (https://www.icpsr.umich.edu/; Deposit number 195624).