The Therapeutic Odyssey: Positioning genomic sequencing in the search for a child’s best possible life

Abstract

Background:

The desire of parents to obtain a genetic diagnosis for their child with intellectual disability and associated symptoms has long been framed as a diagnostic odyssey, an arduous and sometimes perilous journey focused on the goal of identifying a cause for the child’s condition.

Methods:

Semi-structured interviews (N=60) were conducted with parents of children (N=59, aged 2–24 years) with intellectual disability and/or developmental delay (IDD) who underwent genome sequencing at a single pediatric multispecialty clinic. Interviews were conducted after parents received their child’s sequencing result (positive findings, negative findings, or variants of unknown significance). Thematic analysis was performed on all interviews.

Results:

Parents reported that obtaining a genetic diagnosis was one important step in their overall goal of helping their child live their best life possible life. They intended to use the result as a tool to help their child by seeking the correct school placement and obtaining benefits and therapeutic services.

Conclusions:

For the parents of children with IDD, the search for a genetic diagnosis is best conceptualized as a part of parents’ ongoing efforts to leverage various diagnoses to obtain educational and therapeutic services for their children. Cleaving parents’ search for a genetic diagnosis from these broader efforts obscures the value that some parents place on a sequencing result in finding and tailoring therapies and services beyond the clinic. Interviews with parents reveal, therefore, that genomic sequencing is best understood as one important stage of an ongoing therapeutic odyssey that largely takes place outside the clinic. Findings suggest the need to expand translational research efforts to contextualize a genetic diagnosis within parents’ broader efforts to obtain educational and therapeutic services outside clinical contexts.

Introduction

The story of Homer’s epic poem The Odyssey has been used in clinical literature since at least 1972 as a metaphor for the difficult “journey” that patients undertake in searching for a diagnosis (Rang, 1972). Originally framed as the Ulysses syndrome, this metaphor was used to highlight the risks of medicalization and overdiagnosis in settings where false positive laboratory results are interpreted to represent a medical condition, leading to unwarranted and potentially dangerous confirmatory testing (Rang, 1972). More recently, particularly in the field of pediatric genetics, the metaphor of the Ulysses syndrome has given way to the metaphor of the diagnostic odyssey to describe the journey that patients—or more often, parents of pediatric patients—undertake in seeking a diagnostic explanation for a challenging medical problem (Tarini, 2007).

The comparison of the experience of parents of pediatric patients with Ulysses’ journey home from the Trojan War is certainly evocative, but it is also revealing. The parents of children with serious undiagnosed conditions often search for years to identify a name and explanation for their child’s condition. This search, like Ulysses’ ten-year voyage, is often marked by seemingly aimless wandering, dead-ends, and drudgery. In its modern usage, then, this metaphor seems to help outsiders to this journey better understand the frustration experienced by the parents of children whose medical conditions remain undiagnosed.

This metaphor is also capable, however, of casting parents’ Odyssean quest in a less empathetic light. Ulysses’ journey was marked not only by drudgery, but also by perils. The term Ulysses syndrome highlighted the dangers that diagnostic tests can create when used injudiciously (Rang, 1972), an apt comparison given that many of the perils encountered by Ulysses resulted from his failure to resist temptation. It was out of mere curiosity, for example, that Ulysses chose not to plug his ears to the call of the Sirens. Clinicians and scientists have similarly raised concerns that parents’ search for a cause of their child’s illness can lead to distress and compound uncertainty. This concern is raised especially in the context of genetic testing, where false positives still occur and where inconclusive results can be extremely challenging to interpret (Harrison & Rehm, 2019; Kiedrowski, Owens, Yashar, & Schuette, 2016). These concerns are compounded by the fact that medical treatment options for genetic conditions, such as pharmaceuticals, are currently limited and thus may not offer benefits to offset these risks (ACMG Board of Directors, 2015; Botkin, 2016). This potential imbalance of risks and benefits has been an enduring concern in the discourse on the use of newborn screening technologies (Tarini, 2007), as well as clinical testing to provide diagnoses – typically genetic diagnoses – for children with unexplained conditions (Clift et al., 2020).

Ethicists and clinicians have raised a separate set of concerns about the search for treatment options that results once the diagnostic odyssey ends with the identification of a diagnosis. In 2008, Mary Ann Baily and Tom Murray expressed concern that providing parents with a genetic diagnosis for their child without a clinical treatment could start them on a journey to find anything that might work—a “treatment odyssey”— including trying expensive interventions of little benefit (Baily & Murray, 2008). Building on this concern, Jeffrey Brosco has recently argued that a focus on providing a molecular diagnosis may have no clinical benefit and may actually cause harm by overlooking the larger journey parents are on. “Many families and their children are not really on a diagnostic odyssey; they are on a therapeutic odyssey,” he argues. “The odyssey is a search for anything that will help their child walk, talk, run, play, learn to read and write and wonder and search for answers” (Brosco, 2018). The observation that parents are seeking therapies to help their child is supported by empirical research with the parents of children with genetic conditions, who seek to obtain therapeutic benefits and services with the goal of helping their child flourish or “live their best possible life” (Makela, Birch, Friedman, & Marra, 2009; Rosenthal, Biesecker, & Biesecker, 2001). On these grounds, Brosco and others have wondered whether the focus of clinicians and scientists on obtaining a genomic diagnosis, with the goal of ending the diagnostic odyssey, is truly family-centered care. Given that families are focused on improving their child’s life, an emphasis on the diagnostic odyssey might miss the mark: “Does it create more stress? Do [families] feel relieved with a specific diagnosis? What are the opportunity costs?” (Brosco, 2018)

In this article, we present findings from interviews with parents of children with intellectual disability and/or developmental delay (IDD). In the context of their participation in a translational research study that used genome-scale sequencing to find a diagnosis for their child’s condition, we conducted semi-structured interviews to examine the multidimensional impact of sequencing on their child and family. However, rather than just describing the impacts of sequencing, parents provided a broader and more longitudinal narrative of their journey that challenged us to reframe existing conceptions of the diagnostic odyssey and therapeutic odyssey. Based on these interview data, we propose a new account of parents’ search for diagnosis as seen through the story of The Odyssey. Specifically, our data suggest that parents’ actions better reflect the positive traits of Ulysses – resourcefulness and ingenuity – than has previously been highlighted. Parents seek various diagnoses, including a genetic diagnosis, as tools that they utilize resourcefully to obtain services and interventions for their child beyond the clinic and especially in school settings. The journey that parents undertake should be understood first and foremost as a therapeutic odyssey, since a diagnosis is merely a means to a therapeutic end. We argue that conventional conceptions of the diagnostic odyssey run the risk of trivializing parents’ efforts and place undue focus on the search for a genetic diagnosis. There is value, we believe, in recasting the search for a diagnosis as one important thread in parents’ broader odyssey to help their child flourish and seeing a genetic diagnosis as one tool that parents seek in their encompassing efforts to identify “anything that will help their child.”

Materials and Methods

Project overview

The HudsonAlpha CSER Study, a member of the Clinical Sequencing Exploratory Research (CSER1) Consortium, was a mixed-methods translational study of the utility of ES and GS (genome-scale sequencing) for identifying a genetic cause in children and adults with intellectual disability. The study included children with IDD in combination with any number of additional features, including dysmorphism, seizures, and autistic features. The study enrolled over 500 families and involved an intervention (ES or GS sequencing of children and available birth parents) followed by parent surveys addressing a variety of outcomes, including impact on perceived uncertainly in the care of the child and parental assessment of the utility of sequencing. Sequencing outcomes have been published elsewhere (Bowling et al.2017; Hiatt et al.2019;Thompson et al.2018), and survey findings will be reported in subsequent publications. This publication focuses on semi-structured interviews that were conducted with a subset of parents selected to represent a broad range of perspectives. The study was approved by the Western IRB and the University of Alabama at Birmingham. All participants provided written informed consent.

Sample and participant recruitment

Families were qualified to participate in the interview study if they had completed a research visit to receive sequencing results, had agreed to be contacted for additional research, and their child was at least two years old at time of study enrollment. Purposive sampling was used to select 60 families representing a diverse set of perspectives within our target population. We sought to overrepresent racial and ethnic minorities, and to include families that received a positive result (pathogenic or likely pathogenic), a variant of unknown significance (VUS), or a negative result (benign or likely benign) for their child’s IDD in roughly equal numbers. In a few cases, families were purposively sought for interviews because their experiences highlighted known challenges encountered in undergoing sequencing. For example, one family was added to the interview sample specifically because the parents had experienced a challenging time clarifying one of their secondary findings unrelated to their child’s IDD. Because we wanted to ensure that positive, negative, and VUS families were represented, we did not utilize saturation as a criterion for concluding data collection and instead set the number of research participants a priori.

Whenever possible, we conducted interviews face-to-face. When an in-person interview could not be arranged, a phone interview was conducted. Interviews lasted 68 minutes on average. They were audio-recorded by the interviewer and transcribed by professional transcriptionists.

Data collection

The interview guide was designed to elicit the experience of parents’ engagement with the sequencing study, starting with their decision to participate in the study and extending through the period following the result disclosure visit. Domains included the families’ past experience seeking the cause for their child’s illness, decision to participate in the study (including reasons for wanting a diagnosis), experience waiting for the findings, experience receiving the finding, experience with selecting and receiving parental secondary findings, and the personal utility and meaning of primary and secondary findings. Interviews were led by study personnel with experience conducting open-ended, semi-structured interviews (CAR and KBB).

Data analysis

Qualitative analysis was conducted using the software tools Atlas.ti 7.5 (Scientific Software Development GmbH, Berlin, Germany) and Dedoose (SocioCultural Research Consultants, Los Angeles, California). Qualitative coding was characterized by a combination of deductive and inductive approaches and proceeded in two rounds (Bradley, Curry, & Devers, 2007; Raskind et al., 2019; Skillman et al., 2019). In the first round, a single coder (CAR) generated a codebook using twenty parent codes drawn from the domains utilized in the discussion guide, added 1,561 child and grandchild codes identified inductively in the transcripts, and coded all transcripts using this codebook. This comprehensive approach generated a large amount of coded data that captured all interview domains and generated several provisional themes. Because the team was interested specifically in the diagnostic odyssey of parents and their perceptions of the utility of results, we undertook a second round of more focused coding. The senior author and a second coder (KBB and JEC) selected a small number of parent codes from the original codebook and added additional child codes to fully capture data related to parents’ diagnostic odyssey and perceived utility of results. The senior author and the first coder evaluated the new codebook for accuracy. The second coder then inductively identified additional child codes in the transcripts, coded all transcripts, and identified three themes from memos created during coding, which the team refined through discussion. Because the team used a single coder for each round of coding, intercoder reliability was not assessed (O’Connor & Joffe, 2020). Findings were organized and analyzed according to the primary result of the sequencing for the child (i.e. positive, negative, or VUS).

Results

We completed interviews with the families of 59 children aged 2–24 years at the time of enrollment in the study. We had targeted interviews with 60 families but stopped one short of this goal due to project timelines. For twenty-six of the participating families, two parents or guardians agreed to participate in an interview. Most of these parent dyads participated together in a single interview, but in one case the parents preferred separate interviews because they were divorced. As a result, a total of 60 interviews were conducted including 85 total adult participants.

Some families included more than one affected child. In these cases, a single affected child was selected to serve as the “proband,” typically the child who was perceived by the parents to be more severely affected. Most interviews were conducted two to six months following the result disclosure interview, but a small number of interviews were conducted on the day of the result disclosure or greater than six months following the disclosure interview to capture the perspectives of families who otherwise would have been missed. Table 1 reports the demographics of parents who participated in interviews, and Table 2 provides a list of the genetic conditions that were identified in the children whose parents were interviewed. For the quotes provided here, the age range signifies the proband’s age at the time of the family’s enrollment into the study.

Table 1.

Demographics of Interview Participants

	Number (%)
Child’s Result, n=59
Positive	21 (37)
Variant of unknown significance (VUS)	17 (25)
Negative	21 (37)
Age of Child at Study Enrollment (years), n=59
2–5	26 (44)
6–11	15 (25)
12–17	15 (25)
≥ 18	3 (5)
Minimum Age: 2 years
Maximum Age: 24 years
Mother’s Perceived Severity of Child’s Illness, n=59
1 (very mild)	1 (2)
2	2 (3)
3	7 (12)
4	21 (36)
5	12 (20)
6	13 (22)
7 (very severe)	2 (3)
No Response	1 (2)
Parent/Guardian Interviewed, n=85
Mother	56 (66)
Father	27 (32)
Related Guardian	1 (1)
Non-Related Guardian	1 (1)
Other	0 (0)
Race of Interviewed Adult, n=85
White	57 (67)
Black or African American	9 (11)
American Indian or Alaskan Native	8 (9)
Other	5 (6)
Unknown	6 (7)
Ethnicity of Interviewed Adult, n=85
Hispanic or Latino	7 (8)
Not Hispanic or Latino	74 (87)
Unknown	4 (5)
Age of Interviewed Adult (years), n=85
18–29	10 (12)
30–39	34 (40)
40–49	29 (34)
50–59	9 (11)
≥ 60	0 (0)
Unknown	3 (4)

Table 2.

Molecular Diagnoses Received by Interview Participant Families^*

Pathogenic and Likely Pathogenic (P/LP) Findings
Condition Name (MIM) **	Gene
9q34.3 duplication syndrome	Multiple
16q24 microdeletion syndrome	Multiple
Coffin-Siris syndrome (135900)	ARID1B
Cornelia de Lange syndrome (300882, 610759)***	HDAC8, SMC3
Distal 10q Trisomy (60 Mb duplication)	Multiple
Early infantile epileptic encephalopathy (613721, 614558)***	SCN2A, SCN8A
Intellectual developmental disorder with autism and speech delay (606053)	TBR1
Mental retardation and distinctive facial features with or without cardiac defects (616789)	MED13L
Mowat-Wilson syndrome (235730)	ZEB2
Noonan syndrome-like with loose anagen hair (607721)	SHOC2
Pitt-Hopkins syndrome (610954)	TCF4
Rett syndrome (312750, 613454)***	MECP2, FOXG1
Smith-Kingsmore syndrome (616638)	MTOR
Spastic paraplegia (610357)	KIF1A
X-linked intellectual developmental disorder syndrome, Snijders Blok type (300958)	DDX3X
X-linked mental retardation syndrome (300850)	DLG3
No associated named condition	GRIK4
No associated named condition (7q11.22, 3 Mb deletion)	Multiple
Variant of Unknown Significance (VUS) Findings
Condition Name (MIM) **	Gene
Autosomal dominant primary microcephaly (617520)	WDFY3
Autosomal recessive mental retardation (618109)	KDM5B
Dravet syndrome (607208)	SCN1A
Early infantile epileptic encephalopathy (615744)	GABRA1
Galactosialidosis (256540)	CTSA
GLUT1 deficiency syndrome, infantile onset (606777)	SLC2A1
Joubert Syndrome (614615)	C5ORF42
Phelan-McDermid syndrome (606232)	SHANK3
Smith-Kingsmore syndrome (616638)	MTOR
No associated named condition****	ANK2
No associated named condition	BAZ2B
No associated named condition	JMJD1C
No associated named condition***	NBEA, NBEA
No associated named condition	PCNXL2
No associated named condition	RPH3A
No associated named condition	SYNJ2

^*Results listed here are those families that had received results at the time of their interview. Several results listed here, notably VUSs, were later upgraded to P/LP through reanalysis.

^**Condition names and reference numbers are from OMIM.

^***We interviewed two families with a child with this condition.

^****ANK2 is also associated with Long QT Syndrome, but in this case the proposed association with a neurodevelopmental condition currently has no name or OMIM entry.

Three themes were identified during the second stage of coding. These characterized the therapeutic odyssey and how parents understood the utility of a sequencing result for their child within that search: (1) Parents seek therapies and services beyond the clinic; (2) Parents require a diagnosis to obtain school services and optimize placements; and (3) Parents leverage a genetic diagnosis in their quest for therapies and services.

Theme 1. Parents seek therapies and services beyond the clinic

In describing the story of their child’s illness, parents distinguished between two paths in trying to help their child. On one hand, many parents talked about their hopes for clinical treatments or finding a cure for their child’s disorder. On the other, parents expressed an overarching desire and obligation to help their child in the here and now. They described the importance of working with professionals in their communities—physical, occupational, and speech therapists and social workers—to help their child function in everyday life and catch up to peers:

I was always hanging on to a little bit of hope that there might be something we can do to more or less fix her. But we now know there’s no way to just overnight fix. It’s just going to have to be, working with her doctors, her therapies, her speech and OT [occupational therapist]. Everybody’s working together as a whole in trying to make her the best she can. [Negative result, 6–11 years]

Although many parents separated the goal of “curing” their child’s condition from the goal of managing symptoms through therapy, at least a few parents perceived therapy as itself a potential “fix” for their child’s condition. This may reflect early uncertainty about whether the child’s condition would prove to be a developmental delay or a life-long challenge:

I think early on, of course there was hope—yeah, we’re going to fix this—[through] therapy, therapy, therapy, therapy, therapy. [VUS result, 12–17 years]

I think along the way, we all figured out there’s probably not an answer for it, but therapy is probably the only solution. [Negative result, 2–5 years]

Access to therapy for children with IDD typically begins during the preschool years. Throughout the United States, state early intervention programs are a key access point for obtaining physical therapy, speech therapy, and occupational therapy without incurring out-of-pocket expenses for families. When children reach the age of three, the public school system takes over as the access point for no-cost therapy to families. Families may also pursue therapy through private practice contexts. Families typically pay out-of-pocket for private therapy but some health insurers may cover these services.

Because most of the children in our study were at least three years old, parents usually discussed their experience with early intervention as a time when they did not have a genetic diagnosis for their child:

She’s had early intervention therapy. Physical therapy, speech therapy, and occupational therapy. She was already doing all of those things. And then we got the diagnosis, so we were pretty much doing all the right things at that point. [Positive result, 2–5 years]

Some families reported having used private therapy as well, but insurer caps on the number of visits created challenges for sustaining this option:

He has coordination issues. We have occupational and speech [therapy]. We wanted to add physical therapy, but we can’t because there’s not enough visits, and we can’t afford it. [Positive result, 2–5 years]

Therapy was, for some families, a pathway to clinical investigation and diagnosis. Several parents reported that therapists were the first to identify symptoms of IDD and route the child into clinical investigation through referral:

Her OT [occupational therapist] really was the one [who] kept saying, “There’s got to be something else going on here because these are not typical behaviors.” [Positive result, 2–5 years]

Theme 2. Parents require diagnoses to obtain school services and optimize placements

The majority of children in our study were school age, and were eligible for speech, occupational and physical therapy through the school, in addition to special education services. However, parents’ relationships with schools were clearly marked by tension and ambivalence. While early intervention services do not typically require a specific medical diagnosis (other than developmental delay), many parents reported that a specific diagnosis is required to meet eligibility criteria for school programs:

Having that diagnosis in hand when you go to the school and say, “Hey, you need this extra help,” is…I mean, you’ve got to have it. [Positive result, 6–11 years]

Parents did not focus their efforts exclusively on obtaining a diagnosis of a specific genetic condition. They made it clear that a clinical diagnosis—a diagnosis given by a physician or a child psychologist on the basis of the child’s symptoms and psychological testing—could also help them achieve their goals in certain circumstances. However, their narratives suggested that a general clinical diagnosis, like developmental delay or intellectual disability, was often not as helpful as a specific clinical diagnosis or a genetic diagnosis to achieve their goals. In our population, autism was the specific clinical diagnosis most often used to meet eligibility criteria, and some parents said that it helped them to obtain school services for their children:

[Our children] had to have some kind of a label, sadly, to get plugged into the system. And that plugged them in and made it where I did not have to take them all the time. [Positive result, ≥ 18 years]

But parents also expressed ambivalence about accepting a school’s label for their child. One family that had excluded autism as a diagnosis for their child was concerned that the school used the diagnosis of autism to ignore important differences between children:

The problem I have with autism, there’s such a big umbrella, and they throw everything underneath it. [Negative result, 12–17 years]

Other parents worried that labeling was potentially stigmatizing or might exclude their child from receiving services:

We were feeling the pressure from school to get a diagnosis, because if we didn’t get a diagnosis, she was going to be labeled “intellectual disability.” And I didn’t like that, because I felt like there was something more. I was just very dead-set against the intellectual disability [label]. [Positive result, 6–11 years]

Even with a diagnosis, many parents mentioned having to battle with the school to obtain therapies or other services that the parents believed would help the child:

We have to go in there and fight those—excuse my language—those SOBs over there. Like we want our daughter to have this and they’re like, “Oh, I don’t know.” [Negative result, 12–17 years]

I had a hard time getting him appropriate services. That was very challenging. You know, the school didn’t want to provide him enough support and adequate support. So that was very frustrating [VUS result, 6–11 years]

Parents had been interested in participating in the study so that they could obtain a genetic diagnosis, often referred to as a molecular diagnosis when it is identified using molecular diagnostics like sequencing, as an additional tool to help obtain school services. It was not evident, however, that it had provided that hoped-for benefit. Parents expressed mixed feelings about sharing a sequencing result with teachers and schools, perhaps reflecting the challenges they encounter in obtaining services in schools:

Her new teacher and therapist before [this one], they don’t know anything about [name of disorder]. You know, it’s not real common. It just didn’t look like [name of disorder]. So we gave up on that and just went with her diagnosis of autism. She got the services she needed at school. [Positive result, 12–17 years]

Another parent scoffed at the idea of sharing her child’s result with the school:

The school that he attends is really bad. So even if I were to tell them, “This is what he has,” they won’t care. And they wouldn’t know what to do with the information anyway. [Positive result, 2–5 years]

Parents also perceived risks in sharing the results. One parent worried that telling the school about her child’s result might disqualify her from the services she currently received:

I don’t want to reveal all my cards to the school. The school has her as learning disability. As long as I can get the school to do what I want them to do for her, without me laying all this other stuff on the table, then that’s what I do. I don’t want them to go, “Oh, well she has a chromosomal disorder. Why are we helping her? You know, this kid over here really could be helped, and [child’s name] can’t.” I don’t want them to pigeonhole her into a spot where they think there’s no hope or little hope. [Positive result, 6–11 years]

Parents from families who shared their child’s molecular diagnosis with the school reported that the schools could not act on the finding. Those parents expressed skepticism that sharing the result might benefit the child:

[Having the result] didn’t do anything for the school. The school has something they could put down for their records say, you know, “[child’s name/name of disorder].” [Positive result, 12–17 years]

Only one parent described a positive response to sharing her child’s molecular diagnosis with the school, saying that the teachers “were all excited” [Positive result, 12–17 years]. However, when asked if sharing the result changed anything in how the school worked with her child, she replied, “No, it didn’t change anything.”

Theme 3. Parents leverage a genetic diagnosis in their quest for therapies and services

Parents also acknowledged the value of having a diagnosis for obtaining non-school services for their child:

If you have a name for something, more doors can open up for your child…because now she’s got that diagnosis. And they can say, “Okay, yes, we know it’s this, we know exactly what to do to provide her the services that she needs.” [VUS result, 2–5 years]

There’s lots of resources available if you have a diagnosis. [Positive result, 12–17 years]

I need to know what is wrong with him, not so that I can blame anybody. If he’s diagnosed with autism, then I can go, “Okay…most people with this issue tend to do this, this and this. These are the therapies that help them. These are the tools [participant emphasis] that help them.” [Positive result, 2–5 years]

In this domain, as well, a genetic diagnosis was not the only kind of diagnosis that parents sought with the goal of guiding services. One family, for example, reported that the clinical diagnosis of Lennox-Gastaut Syndrome, a diagnosis typically made using clinical symptoms and electroencephalography (EEG), was helpful for obtaining services:

Social Security has labeled Lennox-Gastaut Syndrome as a permanent disability, so we don’t have to go through a bunch of hoops. I didn’t have to appeal anything. I had “Lennox-Gastaut.” So it was like yes, you’re approved. I don’t care what you call it as long as you give her what she needs, you know? [VUS result, ≥ 18 years]

Similarly, parents felt a clinical diagnosis like autism was valuable because it helped them meet eligibility criteria to obtain services at low- or no-cost, or alternatively, it would help a therapist to tailor services to the child’s specific needs:

Father: If your child has autism, there’s all kinds of resources you can go to. Mother: And special schools you can send them to. [Positive result, 12–17 years]

But there also was evident expectation by parents in all result groups that a molecular diagnosis obtained through the study might be helpful in their quest for services. Several parents said they had entered the study hoping for a sequencing result that would classify their child with a specific diagnosis so that they could know how to help their child. One family compared sequencing with identifying which type of cancer a patient has. They characterized the molecular diagnosis provided through the study as a tool they could share with the child’s supportive therapists to target the child’s symptoms:

I guess it all boils down to being more targeted with what therapies we can seek out for him. But it’s kind of like saying, “Okay, so and so has cancer.” Okay, well that opens a broad spectrum of things that you can do. And it kind of breaks down everything, so we can focus on what’s going to work for him. [Positive result, 2–5 years]

Yet this family was also unsure whether their child’s therapists would be able to act on the information:

When I told the therapists, they were like, “I don’t think I’ve had anybody with this before.” [Positive result, 2–5 years]

Some parents who received uncertain sequencing results felt this information could provide utility in their efforts to tailor therapies. One parent in the VUS results group expressed hope that having information about their child’s possible molecular diagnosis might translate into specific therapies in the future:

It makes it better, because if we ever proceed on down that road of learning more about the mutation, or if one day, “Hey, here is this mutation. Here is this therapy that we can do for this mutation and make it better.” [VUS result, 2–5 years]

Some who received a positive sequencing result were able to leverage that result into direct benefits. One parent said that her child’s sequencing study result connected her to a network of rare disease patient advocacy organizations, parent support groups, physicians, and information:

It’s like the world just opened up. They gave us some information about [name of foundation for child’s disorder]. I went straight home, got online, and signed up. The next day, I had someone from that foundation call me. So it was this influx of information. Then, [name of referring physician] said, “[name of specialist] is just down the road. You’re going to want to see him. He’s going to really be able to help you.” What else? Being able to find assistance for her that we had never been able to get before. That was huge, because it was so hard to pay the medical bills and the medicine. [Positive result, 12–17 years]

Another parent from the positive results group had not discovered a way to leverage the molecular diagnosis into tailored therapies, but expressed confidence that the diagnosis could provide this benefit:

I can find other families, other people who had to deal with this. And I can get help in, “OK, well, this therapy worked for this one or, this one lived to be 30, or everybody that’s ever had this lives to be 25.” Now I can have a goal to actually research and find out information on [this variant], versus, “Well, this is the 500 million people who got [cerebral palsy] and they range anywhere from croaking at two years and living to be 200.” [Positive result, 2–5 years]

Discussion

During open-ended interviews with parents, we invited them to tell us about their child, beginning with the moment they recognized a problem, up to the present day, after they had received findings from the study. We wanted to know what hopes they had for clinical investigation of their child, why they decided to undergo genomic sequencing, and what utility, if any, a sequencing result has provided. Parents told us they hoped that sequencing their child would give them an answer and would help them plan for the future. Receiving a sequencing result met emotional and information needs, including relieving guilt, connecting them to other parents, and offering hope for future clinical treatments. In these ways, parents’ longitudinal narratives about their journey echoed findings from other researchers about the clinical and personal utility of pediatric exome sequencing (Malek et al., 2017; Nguyen & Charlebois, 2015; Sawyer et al., 2016; Vissers et al., 2017).

Even though we had structured the interview guide to focus on the genome-scale sequencing delivered through the study, parents positioned the potential for finding a molecular diagnosis within a much broader story about their efforts to help their child flourish. These stories were characterized by efforts to obtain one or more types of diagnoses –clinical, functional, and genetic diagnoses – as tools to obtain additional therapies and services or to better tailor services. The search for additional diagnoses often took the form of obtaining more specific or refined diagnoses. Parents frequently reported that more specific clinical diagnoses, such as autism, had previously proven useful for meeting these aims, but also desired a genetic diagnosis to meet additional goals. They expressed hope that professional therapists working with their child would know what to do with this diagnosis and perhaps even tailor therapies to that diagnosis. On this, our findings echo previous work indicating that parents are aware that not all diagnoses for a child with IDD afford equal access to services (Makela et al., 2009). However, parents in our study often valued having several specific diagnoses (such as a clinical diagnosis of autism and a molecular diagnosis of Smith-Kingsmore Syndrome caused by pathogenic variants in MTOR), rather than prioritizing one over the other as has previously been observed (Makela et al., 2009). Parents were also clear that these specific diagnoses are much more useful in their efforts compared with descriptive labels like IDD.

Parents also reported that a molecular diagnosis obtained through the study was useful in that it had allowed them to connect with other parents in disease-specific support groups and rare disease networks (Barton, Wingerson, Barzilay, & Tabor, 2019; Nicholl, Tracey, Begley, King, & Lynch, 2017; Skinner & Schaffer, 2006). These communities provide support for parents, in that members understand one another’s struggles. Perhaps even more importantly, though, these communities provide a forum for sharing wisdom about navigating the parental role, working with healthcare providers, and finding therapies and other interventions that have worked for other children with the same condition.

Taken together, our findings suggest an unexpected framing for the role of genetic and genomic testing in the journeys of families who have a child with IDD. In the conventional framing utilized by many translational genomic researchers, the metaphor of the diagnostic odyssey focuses narrowly on parents’ efforts to obtain a genetic or molecular diagnosis. Once parents obtain this diagnosis, the diagnostic odyssey gives way to a therapeutic odyssey, characterized as a search for medical interventions within clinical settings that can help improve a child’s health outcomes. But the story for parents does not appear to be that dichotomous—or that localized to clinical settings.

If we recall Jeffrey Brosco’s account, he challenges us to see that parents are primarily on a therapeutic odyssey, searching for “anything that will help their child walk, talk, run, play, learn to read and write and wonder and search for answers” (Brosco, 2018). Our findings support Brosco’s framing, that parents are primarily on a therapeutic journey. However, our findings also suggest that the scope of parents’ action and purpose is more expansive than his account might indicate. For Brosco, a diagnosis is likely to be of more interest to a child’s physicians and does not further parents’ pursuit of therapeutic options. He suggests that offering genome-scale sequencing to parents is potentially burdensome because parents are actually on a therapeutic odyssey. Therefore, sequencing results will not have utility to parents in this search. Our findings suggest that this assumes an unwarranted distinction between the diagnostic and therapeutic searches, while privileging clinical therapies and overlooking the other potential benefits that parents may obtain with a diagnosis, including a genetic or molecular diagnosis.

We suggest that it is more accurate to think of the parents’ entire journey as a therapeutic odyssey rather than a diagnostic odyssey, with the diagnosis as a tool to search for services and interventions for their child, usually beyond the clinic. In the language of Claude Lévi-Straus, parents are “bricoleurs” (Lévi-Strauss, 1966) who are resourcefully piecing together a multifaceted strategy for their child to give them their best possible life. In terms of the comparison with Ulysses, the conventional framing risks emphasizing the pitfalls that result from mere curiosity. We believe this change in language is important because cleaving parents’ search for a genetic diagnosis from their broader search for therapies and services obscures the value, for some parents, of using a sequencing result to find therapies and services and tailor them to their child’s needs. The focus on the diagnostic element of this journey also impairs our understanding of parents’ aims because it focuses on the means rather than the ends, the tool rather than the project. In this way, we fear that the conventional framing of the diagnostic odyssey has had the effect of trivializing parent’s desire for a genetic diagnosis, in that this desire has not been appropriately contextualized within the larger commitment and work of parenting a child with intellectual disability or another rare disease. Our findings suggest an opportunity to instead emphasize the Ulyssean cunning and resourcefulness that also marks parents’ efforts.

For translational researchers examining the utility of sequencing in pediatric contexts, our findings draw attention to the importance of investigating how actors and institutions outside medical centers interpret and use sequencing results. Parents take their therapeutic odyssey wherever they need to in order to help their child. This includes efforts taken with healthcare providers in the clinic, but also outside the clinic with professional therapists, early intervention programs, and schools. Given the role that these professionals play in helping the child, there is value in understanding the utility and outcomes that families experience when they share a genetic or molecular diagnosis with these therapeutic and educational professionals. In particular, it would be important to understand whether a molecular diagnosis is as effective at improving access to therapies and services as parents hope that it will be. It is also critical to understand how professionals in educational and therapeutic settings interpret and use a genetic or molecular diagnosis in their interactions with a child. Given that sequencing will increasingly be utilized to provide a molecular diagnosis for children with IDD, it will be important to adopt a more inclusive framing for translational research that includes these professional. This work will take both empirical curiosity and a commitment to a family-centered perspective, which means looking at parents’ efforts to improve their children’s lives wherever they take place, and asking how parents navigate the organizations and institutions that help their child function and thrive.

Limitations

Although all interviews were conducted in English by monolingual interviewers, participants in two interviews responded to some questions in Spanish. When this occurred, their spouse, who was more comfortable speaking English, interpreted responses in real time for the interviewer. To improve accuracy, we contracted bilingual transcriptionists to translate these audio-recorded Spanish-language responses into English. Given that these interviews were conducted primarily in English, which was not the preferred language of these participants, we ensured that key insights were not based on these translated comments.

Conclusion

Our findings suggest that receiving a genetic or molecular diagnosis for a child with IDD is like one of the episodes recounted in The Odyssey – navigating between Scylla and Charybdis or escaping from Polyphemus’ cave – but does not comprise the whole of parents’ odyssey. This broader project takes the form of a therapeutic odyssey, which involves parents seeking benefits, services, and therapies for their child through a variety of settings, including through work with educational and therapeutic professionals. The therapeutic odyssey focuses on parents resourcefully seeking and utilizing various diagnoses to achieve a variety of aims, all in service to the goal of helping their child flourish. Research on how professionals in educational and therapeutic settings interpret and use a molecular diagnosis will advance our understanding of the potential broader meaning of pediatric sequencing for families.