Negotiating the Diagnostic Uncertainty of Genomic Test Results

Return of Exome Sequencing Results

The genetic consultations have as their primary purpose the communication of the exome sequencing results to families. These clinic visits represent the end point of a process that began when a pediatric geneticist ordered exome sequencing to determine whether there was a genetic basis for the child’s phenotype. Using blood from the child and typically both parents, exome sequencing analyzes the protein-coding portion of the child’s genetic material (the exome) with a focus on genes that are known to be associated with one or more of the child’s symptoms.

Following testing, the laboratory analyzes the exome data at a genetics data board meeting to determine which results, if any, should be interpreted as causal (Lee et al. 2014). To capture the broad interpretive range of exome findings, the American College of Medical Genetics and Genomics recommends the use of five genetic test result categories depending on whether the genetic variant a test identifies should be interpreted as causing the patient’s symptoms: A variant is either benign, likely benign, pathogenic, likely pathogenic, or of uncertain significance (variant of uncertain significance, VUS). ² Few labs report benign or likely benign polymorphisms since these variants have little clinical value, and we have no cases of these categories being discussed. A pathogenic variant refers to a known, published variant associated with a similar phenotype to the patient. This is treated as an unambiguous genetic cause. A likely pathogenic variant falls short of the strong correlation of a pathogenic variant but is more likely than not involved in the patient’s phenotype (e.g., the exact variant has not been published, but the gene has been associated with the patient’s phenotype). Finally, and most interestingly, a variant of uncertain clinical significance is a variant that was definitely found in the child, but current evidence is unclear in whether the variant should be interpreted as causing the child’s symptoms. A VUS has both strikes in favor and against causality, but the team considers it sufficiently suggestive of causality to include in the report. The laboratory report contains a brief narrative specifying the reason(s) for inclusion and how the variant falls short (Timmermans, Tietbohl, and Skaperdas 2016). The expectation is that when more knowledge becomes available over time, the VUS can be reclassified as either benign or pathogenic.

Once in the consultation, the geneticist and genetic counselor deliver the laboratory results with a copy of the report in hand (see Figure 1).

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Figure 1.

Illustration of How Report is a Point of Reference During the News Delivery

The report lists each genetic variant and its location in the genome with the laboratory’s interpretation of whether that variant is causal of the child’s symptoms highlighted at the top of the report—Pathogenic, Likely Pathogenic, or VUS—followed by an explanation. Parents receive a copy of the highly technical report at the end of the consultation. ³ While clinicians summarize each section for parents and may point to the sections they are reviewing, parents typically do not utilize the report as grounds for their own questions during the consultation but react to the verbal communication.

Despite the presence of a detailed report, geneticists do not simply operate as conduits of the laboratory. Rather, another round of interpretation occurs in the clinic consultations, and this interpretation is shaped by parent participation. Similar to the ways that clinicians can prescribe drugs off-label, geneticists can interpret variants from the report in ways that differ from the write-up. We document how clinicians interpret VUS as likely causal or unlikely causal of the child’s symptoms; how parents challenge, question, or alternatively support an interpretation; and how this affects clinicians’ interpretations of certainty. We show that parent behavior is consequential for the genetic diagnosis outcome of the visit, leading to a collective upgrade or downgrade of certainty over the course of the consultation. This both allows parents to negotiate a different take-home interpretation and facilitates a collective reduction of diagnostic uncertainty.

Reinterpreting Genetic Variants

When communicating VUS results, geneticists may simply report the causal ambiguity as reflected in the report. This happened in 44 percent (16 out of 36) of the VUS results discussed. In these cases, clinicians follow the report closely and minimally exert their own perspective. They state both the pros and the cons of interpreting causality without revealing what they think the variant is doing in the patient. The high frequency is likely due to tremendous heterogeneity in the VUS category. Laboratories use the VUS category to include variants about which almost nothing is known and others that are quite promising but fall short of having strong causality criteria. In many instances, the geneticist would have no basis for independently interpreting the variant. An unintended consequence of this behavior is that physicians provide no access to their interpretation of the exome sequencing results. Thus, in these cases, parents may have difficulty participating in the construction of a take-home genetic diagnosis.

Geneticists, however, go beyond the report in 56 percent (21 out of 36) of VUS cases. They exercise their right and authority as diagnosticians to upgrade in 31 percent (11 out of 36) or downgrade in 25 percent (9 out of 36) of VUS cases. With “upgrading,” we refer to the geneticist’s presentation of the variant as causal or likely causal rather than ambiguous; with “downgrading,” we refer to their presentation of the variant as not or unlikely to be causally involved in the patient’s phenotype. ⁴ Both up- and downgrading offer greater certainty than is implied by the report’s identification of a variant of ambiguous causal status.

Extract 1 provides an example of an upgrade. The infant in this case was born deaf in both ears. The clinician states that the report identifies two changes in a gene that is associated with deafness (Lines 1 and 2). He then goes on to state that there was a genetic contribution by each parent (Lines 2/4). Next he paraphrases that “it say:s tha:t,” then qualifying with “in some papers which we ha:ve” this gene is associated with a recessive form of deafness. At this point, the clinician has not yet overtly adopted a stance that he believes the variant to be causal. He has merely summarized the report and asserted an association based on “some” scientific articles. However, shortly thereafter, he explicitly states this as his belief (Lines 34–36).

OPEN IN VIEWER Extract 1

In this case, as in all cases discussed in this article, the report identifies that a given variant in a gene exists but also that it is uncertain whether this variant represents a genetic diagnosis of the deafness—that is, it is uncertain whether the variant caused the child’s deafness. Despite the report’s inherent uncertainty regarding the variant’s causal relationship to the child’s deafness, the clinician departs from the report to propose that this variant should be interpreted as likely causal: We suspect (Line 34) and then the initiation of repair with the insertion of “very very strongly” in Line 35 (Schegloff 2013) “that this is what’s causing his hearing loss.” (Lines 35–36). In suggesting that this variant should be interpreted as causal, the physician invokes his own knowledge about the genes involved to account for his departure from the report.

The upgrade is also done authoritatively in terms of voice quality. At Line 34, the clinician begins rather dysfluently and with a creaky voice, but at the beginning of “suspect,” he moves to modal voice, and at very very strongly, he has transitioned to a regular tempo of speech. Reviews of the function of creaky voice (Mendoza-Denton 2011; Sicoli 2010) reveal wide-ranging associations, yet here the combination of shifting from creaky voice into modal (“normal”) voice and out of dysfluency may increase the strength with which the parent hears the upgrade. Upgrades vary in how strongly they are asserted, ranging from definitely to likely causal.

Clinicians also act as independent diagnosticians when they downgrade the variant by reinterpreting a reported VUS as unlikely to be causal. In Extract 2, the report identifies three variants, which could be associated with the child’s neurological and immunodeficiency symptoms. But as in Extract 1, the report identifies the relationship between the genetic variants and the child’s symptoms as uncertain. When the report contains several VUS or a VUS combined with a likely pathogenic or pathogenic variant, geneticists tend to rank the variants and downgrade the VUS that least fits the child’s phenotype, or about which less is known.

In Extract 2, Lines 1–2, the geneticist introduces the first variant in the gene (“it”) that the report identifies as possibly causing the boy’s symptoms. Yet the clinician downgrades the initial genetic variant from its uncertain status in the report to an interpretation that it is not causal: I don’t think [is] significant in what Joey has (Lines 18–19).

OPEN IN VIEWER Extract 2

The geneticist distances himself from the report, suggesting that the laboratory was wrong to report the variant (Lines 9-13). He proposes that the parents “forget” about it (Line 18). It is also significant that the typical case is described with what “we” do, situating the clinician as part of a larger team (Drew and Heritage 1992; Heritage and Maynard 2006), but when it comes to the actual interpretation of this particular variant for this patient, the reference is to “I.”

Although up- and downgrading the ambiguous variants relative to their status in the report is a clear assertion of the clinician’s authority as a diagnostician, clinicians do not baldly assert up- or downgrades. Rather, they pair them with accounts (Heritage 1984), leading to a careful balance between authority and accountability (Peräkylä 1998, 2002). These accounts provide insight into the physician’s thinking process and evidence to the parent(s) that this interpretation is the correct take-home interpretation. Accounts reveal the grounds of the clinician’s authority and expertise. As Peräkylä (1998, 2002) has shown, diagnoses that include accounts provide patients and their caregivers with grounds to possibly question the diagnosis. In these data, geneticists back up their interpretations with evidentiary reasoning and expert genomic knowledge (see Extract 3). As in other cases, here the report documents the presence of a genetic variant, but it asserts that it may or may not be causal of the child’s symptoms. In contrast, the physician concludes that it is causal. At Line 1, the clinician is summarizing the three reasons why he believes the variant is causal of the child’s symptoms. We see the actual upgrade in Lines 17–19: We conclude that most likely this gene is one of the reasons why she has the symptoms. While there are markers of caution with “most likely” and “one of the reasons,” the interpretation is nonetheless clearly that the genetic variant is causing the child’s symptoms.

OPEN IN VIEWER Extract 3

In providing a three-part account, the clinician offers insight into the reasons why he departs from the report in his conclusions and works to justify his interpretation of causality (Lines 2–14). Lists are known to have rhetorical force, so this may also be persuasive (Jefferson 1990). Moreover, in building up to a conclusion, the clinician starts to delineate known causal ambiguity from unknown causal ambiguity: The rarity of the variant is actually positive evidence that the variant may be causal for this unique set of symptoms, while a statistically derived prediction that the variant will be pathogenic coupled with the fact that other parts of the gene are known to cause related symptoms add up to strong circumstantial evidence that the variant is causal. The remaining ambiguity is that this specific variant has never been directly identified in someone with the patient’s symptoms.

If we return to Extract 1, the physician also accounts for his interpretation of upgraded causality. In that case, the physician declares that in some papers . . . two mutations in this gene are associated with autosomal recessive deafness (Maynard 2004). In this situation, the family is African, and the variant is common among African Americans, which would be a strong strike against interpreting causality for that population (but not necessarily for Africans). In fact, the exome team filters out variants that are common in the relevant population because these are not expected to cause exceedingly rare symptoms. To interpret this variant as causal, the clinician must justify how a variant that is common across a population explains a rare disease. In Extract 1, he does that by arguing that the variant has variable penetrance: In some people, it leads to symptoms; in others, it doesn’t (data not shown). This rationalization, however, comes after the geneticist has marshaled the strongest possible evidence in favor of causality—articles in the medical literature (some papers). Before the geneticist discusses the VUS status, he has already clinched the case for causality.

Physicians also typically include accounts when they downgrade a report’s interpretation of a genetic variant from a VUS to a variant that is unlikely to be causal. In Extract 4, the clinician reviews a variant that is autosomal dominant (meaning that the child only needs to have a genetic variant from one parent—not two as in a recessive condition mentioned earlier—to show symptoms). The clinician’s downgrade occurs when he states that the variant “is not likely to be causal for her disease.” However, prior to the downgrade, the physician accounts for his position by arguing that although variants in this gene have been associated with the patient’s phenotype, the exact variant has not been seen, and the father has this same variant but is asymptomatic. Consequently, these two facts make it unlikely that the variant is causal. Note again that such accounts are not part of the report but are provided in the context of the clinician’s reinterpretation.

OPEN IN VIEWER Extract 4

In this case, the geneticist quite explicitly differentiates his interpretation from the report when he says, So it’s reported here, but is not likely to be causal (Lines 14–15). Thus, the clinician asserts his own expertise to downgrade the variant’s causal status in the report, but he does not do so unilaterally. He provides insight into the logic behind his reinterpretation based on the fact that father and daughter share the variant, but the father is asymptomatic.

Extract 2, shown earlier as a downgrade, also included an account for the physician’s reinterpretation. In particular, the physician stated that no one else in the world has had mutation there (Lines 7–8) and later that he didn’t know how to interpret the variant. The geneticist further distances himself from the laboratory report by asserting annoyance at the lab for reporting this variant.

In this section, we have shown that clinicians invoke authority as health professionals in exome sequencing results consultations when they depart from genetic causality interpretations in the laboratory reports through upgrades or downgrades of the causal status of genetic variants. Instead of reporting an ambiguous finding, an up- or downgraded take-home interpretation provides parents with a greater degree of certainty either through a more conclusive exome finding or through a more bounded degree of causal ambiguity than existed prior to the exome sequencing consultation. Additionally, when clinicians up- or downgrade report findings regarding causality, they orient to the relevance of parent support for their logic. The provision of greater insight into the physician’s reasoning process through accounts can be a persuasive resource to bring parents to the clinician’s view (Heritage and Stivers 1999), but it also allows parents greater ability to support or challenge the conclusion. For parents to feel that a genetic diagnosis is certain to be causal (or certain to be not causal), they must both understand the interpretation and believe it. The opportunity to support or challenge the assessment has been shown by Maynard (1989, 2003) to increase acceptance of diagnostic test results.

Parent Questioning

Clinicians do not necessarily have the last word on a variant’s interpretation. Their up- or downgrade coupled with an account invites parents’ engagement with the interpretation. Through their interventions, parents also contribute to clarifying the boundaries of ambiguous causality, shape the interpretation of the variants, and bring their own agenda to the situation. Their interventions are not mere curiosity questions but reflect underlying social-psychological concerns with diagnosis and prognosis. In response, clinicians have an opportunity to address both immediate questions about causality and parents’ deeper existential concerns related to diagnostic uncertainty. We review three ways parents consistently engage physicians’ accounts in these data: supporting, challenging, and questioning.

First, we can see evidence that a parent supports a genetic account in Extract 5. Here, the child has presented with both joint laxity and pain (possibly indicative of Ehlers-Danlos or Marfan Syndrome) as well as Arnold Chiari malformation, characterized by structural defects in the cerebellum. Exome sequencing identified a genetic variant that could be associated with Ehlers-Danlos Syndrome (classified on the report as a VUS). The physician observes that the presence of the same variant in the father poses a “little problem” (Lines 4–5) for a conclusive genetic diagnosis because upgrading the genetic variant to causal of the child’s joint problems would require explaining how the same variant could be present in an asymptomatic parent. Recall that the same situation of an asymptomatic parent and a symptomatic child was grounds for downgrading the genetic variant of the child’s symptoms in Extract 4. The way the clinician gives parents access to his reasoning about the variant provides them with the grounds to contribute to the take-home interpretation (Peräkylä 1998, 2002). In Line 7, the clinician unpacks the causality problem further in his initial inquiry about whether the father has symptoms, designed as a negative declarative for confirmation (Labov and Fanshel 1977). The father instead disconfirms, stating that he does have pain in certain joints. Although this is a disconfirmation of the question, it works to support a genetic diagnosis of a variant in the COL5A1 gene as causal of the clinical diagnosis of Ehlers-Danlos Syndrome insofar as the father is now implicated in an affirmative genetic diagnosis (Maynard 1992).

OPEN IN VIEWER Extract 5

The clinician appeared to be inching toward a downgrade of this variant based on the father sharing the variant and presumably being asymptomatic, similar to the clinician in Extract 4. Yet when the father claims that he actually has pain in his shoulders (Lines 19–21), the geneticist switches course and effectively offers support for upgrading the variant as pathogenic: He accepts the father’s response with “Okay” (Line 25) and then offers an upgraded interpretation that could be an explanation (Line 25)—a clear change in position from prior to the father’s intervention. Slightly later the geneticist continues more strongly with “I: think that it- it’s uh decent fi:t.” (Line 54) though “I can’t fully pr^ove it” (Line 55). The emphasis through the sharp pitch rise on prove suggests that setting the bar that high is not necessary for the upgrade to causality.

Importantly, the parent’s contribution reduces what is unknown about the child’s condition, thus potentially lessening the psychological burden of uncertainty. Rather than leaving the joint laxity and pain genetically unexplained, the variant may indeed be causal. Geneticist and parent together construct a more certain conclusion than would have been expected at the outset of the clinician’s description of the laboratory findings. What could have been a counterargument for causality (that the father is asymptomatic with the same variant) instead strengthens the case for causality (father and daughter share the same variant and similar symptoms). The question-and-answer intervention (Lines 17–21) both facilitates the father’s participation and allows him to shape the certainty of the take-home interpretation. Together, clinician and parent construct the degree of causality that this genetic variant is understood to have. This may reassure parents with regard to underlying concerns about the genetic diagnosis of their child’s condition.

A second way that parents can shape the interpretation of a genetic variant is through challenging an account, thereby indicating disagreement with the clinician’s interpretation. Extract 6 shows an example. The patient is a young adult accompanied by her mother. The geneticist has reported a number of variants related to the patient’s major symptoms. At this point in the news delivery, the clinician shifts over to discussing possible causal variants of one symptom: excessive bleeding during menstruation. The report contains two VUS. The first is known to affect the platelets so that they do not bind, and thus, the body bleeds longer than it should (data not shown). The physician does not explicitly upgrade the VUS to likely causal of the young woman’s symptoms; however, he implies possible causality insofar as he offers a test to confirm whether there is a problem with the platelets (Line 4). His use of to confirm implies that it may well be causal. The physician goes on to offer a counterhypothesis—that the patient does not have the second necessary variant for a recessive gene to cause the problem (Lines 9–11) but then provides yet another counter argument that we missed the other change on the other copy (Lines 11–12). Ultimately, the physician’s position suggests sufficient reason to think this is likely causal to warrant a follow-up test (Lines 26–27). The mother challenges this position when she begins to ask—and ultimately asserts—this is the only bleeding issue she’s ever had (Lines 31–32).

OPEN IN VIEWER Extract 6

The mother’s challenge of the genetic diagnosis begins as a negative interrogative—a format known for its strongly assertive properties (Heritage 2002). This is repaired twice in order to ultimately articulate a fact about her daughter’s history that poses a problem for interpreting this genetic variant as causing a platelet disorder that leads to excessive bleeding. In response, the patient agrees with her mother (Line 33), and the physician claims agreement as well with Exactly and then goes on to adopt a stance that is at odds with the one implied earlier that it could be causal. He effectively downgrades the variant as unlikely to be causal: That’s why I’m not that suspicious (Lines 34–35). Both in the consultation and in our post-consultation interview, the mother suggests that a systemic coagulation disorder would likely have been discovered years ago because her daughter had many surgeries. The clinician knows this from her medical record and the history that was taken prior to the exome test being ordered. This reasoning by the mother reflects her high level of cultural health capital (Shim 2010), honed through years of interaction with medical professionals for her daughter’s many problems. But it is not unique to this family. Parent challenges occur throughout the dataset.

Parents thus can shape the take-home interpretation of results through challenging a position that particular variants are likely (or unlikely) to be causal of the phenotype by bringing their experience-based logic to the situation. Moreover, these challenges are facilitated through the insight that clinicians provide parents into their own diagnostic reasoning. In Extract 6, if the variant was the genetic cause, it could have life-changing consequences for this family. Thus, the mother’s challenge brings an abstract discussion of causality down to the exigencies of the situation. These challenges, like displays of support, work to bring clarity to what is otherwise ambiguous.

Third, one of the most overt ways that parents shape the take-home interpretation is through directly questioning the clinician’s certainty. When posited after a geneticist’s claim of relative confidence, these inquiries work to pin clinicians down to an even greater level of certainty than they were otherwise offering. Thus, parent questions pursue reducing the social psychological burden of uncertainty. In these cases, however, clinicians recurrently retreat to a less certain interpretation, thus leading to further oscillations about the variant’s causal role in the diagnosis. For instance, in Extract 7, a clinician has offered multiple accounts for why the genetic variant should be interpreted as likely causal of the patient’s symptoms. He ends with “this may:: be thuh cau:se of what she has.” Although the modal may is heavily stressed and stretched, suggesting less than full confidence, the upgrade to causal status remains and occasions the mother’s request for confirmation: “It was definitely the reason why she has that?” (Line 9). This question works to secure more definitive certainty in a context where the physician has already moved from uncertain (VUS) status to likely causal status. Yet, in response, another member of the genetics team downgrades with “°No.we can’t (say) sure°”—though this is done in very low volume. The trainee accompanying the geneticist is also shaking her head.

OPEN IN VIEWER Extract 7

The mother pursues increased certainty further with an extension of her question, offering an alternative causal explanation—Or was it the congenital hypothyroidism (Line 12)—likely referring to a previous biomedical explanation for her daughter’s problems. The physician first responds with “W’ll we don’t know that” but then introduces different causal possibilities, thus complicating the picture that he had been painting of a likely causal pathway between the variant and the child’s phenotype. For the patient, the difference between congenital hypothyroidism and the genetic variant suggestive of improper brain function is highly relevant because each implies a different therapeutic course.

This pattern of parents questioning clinicians’ certainty and clinicians retreating to reduced certainty recurs across the data but is most apparent in cases involving physician upgrades. In these situations, physicians have generally already accounted for their stance that the genetic variant should be interpreted as more likely causal than the laboratory report suggested. Parents’ questions in these contexts reveal several key issues: (1) parents question physician authority, even when the disparity of knowledge is pronounced; (2) given the relative infrequency of these questions in downgrades and ambiguous interpretations, upgrading causality facilitates parent participation; and (3) when parents ask these questions, they shape take-home interpretations insofar as physicians routinely scale back their upgrades of genetic variant causality to ambiguous or even unlikely status. Drawing on their own observations and experiences, parents then call the physicians on the strength of their clinical logic.

In this section, we have provided evidence for how parents’ support, challenge, or questioning of VUS interpretations as either causal or unlikely to be causal shapes the take-home interpretation of the variant. In these interactions, parents take the arguments the geneticists used to shore up their interpretation as prompts to draw out the next logical implications or to question and push back against the certainty. At this point, physicians hesitate and often retreat by reintroducing grounds for causal ambiguity. Occasionally, parents’ questions strengthen an upgrade when the physician uses the opportunity to restate the reasons in favor of causality. In all instances, the causal status of the variant has oscillated in response to the parents’ interventions, and this may lead to further deviations from the VUS interpretation reflected in the laboratory report. At the end of the consultation, the geneticist and parents have clarified how the variant falls short of being clearly causal of the patient’s symptoms and what additional knowledge is needed to assign causality in this specific patient. The final understanding of a genetic cause as certain or how the variant plays out in the specific patient is best understood as an interactional achievement, not only different from the laboratory report but also different from the agenda set out by the clinician when initially presenting the results. At the same time, this collaboration works to reduce the burden of causal ambiguity and pushes clinicians to be more definitive.

The Reception of Ambiguous Genomic Test Results

How does this interactional exchange clarifying and specifying genomic ambiguity help assuage the broader diagnostic uncertainty parents experience due to not knowing what has caused their child’s symptoms? By giving parents access to their reasoning, opening the interpretation up for questioning, and delineating what is known, we propose that clinicians offer parents an opportunity to channel their deeply felt concerns. Parents consistently pose questions that reflect social psychological burdens: fears about prognosis, quality of life, and implications of the genetic variants. Even lacking conclusive answers, geneticists work to address parents’ underlying existential concerns. This is the clearest in instances when geneticists retreat from previous causal claims (e.g., Extracts 6 and 7). Rather than addressing an abstract question of a match between a child’s symptoms and their genetic material, geneticists’ readiness to retreat reflects their realization that parents have a stake in the match in their child. In moving beyond the questions being asked to larger concerns the questions represent, geneticists convey that even though the test failed to turn up a conclusive genetic cause, the genetics team will remain committed to the family. The conversational structure of the consultation thus not only creates certainty out of uncertainty but also makes the most of causal ambiguity—something that may be comforting to parents.

To bolster this interpretation about the reassuring reception of ambiguous results, we turn to interview data. We asked parents to reflect on the news delivery and the relevance of the genetic findings. Not surprisingly considering that families had either requested or agreed to exome sequencing, respondents typically indicated that it was better to know than not to know what caused their child’s condition. Still, families did not always receive the news they were hoping for: Exome sequencing failed to reveal a genetic cause, identified new conditions and risk factors, or revealed a progressive or terminal condition. Even then, no respondent told us that they regretted undergoing exome sequencing. Instead, they remarked that not knowing was “nerve wracking” (C4), “frustrating” (C13), and “stressful” (C19) and that “we want to know what’s really wrong with us” (C32). Although no parent gave examples of how a genetic diagnosis changed the daily care for his or her child, parents who received a genetic diagnosis stated that “it’s just nice to have that solid knowing what it is, versus not knowing” (C3) or “the more information the better, is how I feel about it” (C9). This last comment is interesting because it came from a parent who challenged the physician, leading to a downgraded interpretation (Excerpt 6).

An upgraded VUS result with lingering causal ambiguities may be reassuring as well. A mother (C26) told us: “We feel relief, that is the word, knowing that Dr. Xang and his genetic counselor, you know his team, were able to tell us, ‘We ran this test, we found a chromosome 6, and it’s these genes’ deficiency.’” This appreciation was not dampened by the realization that the geneticists “don’t know if it caused it or not, but it could be a possibility cause.” Instead, she explained that the geneticists told her that her son was a unique and atypical Ehlers-Danlos patient who needed physical therapy. Still, she added, “At the same time, it is a little bit frustrating knowing that what happens inside of him is unpredictable because it’s tissue related and collagen.” In the end, however, she reiterated, “We’re thankful for the clinic. I think that we know what we’re dealing with, Dr. Xang, the genetic counselor they counseled us clearly, but they did let us know that they did not know much about this kind of Ehlers-Danlos, it’s more like type 3 hypermobility.”

This mother, like many parents, picked up on the lingering ambiguities in the news delivery, but by parsing what is known from what it is still unknown, she was able to find comfort in the news delivery. A different parent stated, “It’s good to have something. I still kind of feel bad because it’s not clear whether or not that’s causing the seizures” (C10). Similarly, a parent expressed in an interview her deeply felt desire for a “normal” child (C3). Considering the many cognitive and physical disabilities, this was out of the geneticist’s reach. He was even unable to produce a genetic diagnosis for her son’s symptoms. He could convey, however, that even if the genetic results remained ambiguous, he was willing to conduct further follow-up tests, keep an eye on the medical literature to see whether more information would reclassify the VUS, and engage the family’s underlying concerns. Geneticists and parents then work together to render genetic ambiguity meaningful—to derive certainty from uncertainty—for the broader existential diagnostic uncertainty concerns that drive the search for a genetic cause.