Assessing parental understanding of variant reclassification in pediatric neurology and developmental pediatrics clinics

Abstract

Improvements in technology used for genetic testing have yielded an increased numbers of variants that are identified, each with a potential to return uninformative results. While some genetics providers may expect patients to be responsible for staying abreast of updates to their genetic testing results, it is unknown whether patients are even aware of the possibility of variant reclassification. Little research has assessed the comprehension and attitudes of parents of pediatric patients regarding reclassification of variants of uncertain significance (VUS). Semi-structured telephone interviews were conducted with parents (n = 15) whose children received a VUS from genetic testing in either the pediatric neurogenetics or developmental pediatrics clinics at Riley Hospital for Children in Indianapolis, Indiana. Most participants expressed understanding of the uncertainty surrounding their child’s VUS test result. However, nearly half of participants shared that they had no prior knowledge of its potential reclassification. When asked whose responsibility it is to keep informed about changes to their child’s VUS status, some participants stated that it belonged solely to healthcare providers — a distinctive finding of our study — whereas others felt that it was a joint responsibility between providers and the parents. We additionally found that some patients desire a support group for individuals with VUS. These results provide insight into the importance of pretest genetic counseling and the need for increased social and informational support for parents of children who receive inconclusive genetic testing results. We conclude that relying solely on the patient or guardian to manage uncertain results may be insufficient.

Introduction

The emerging use of multigene panel sequencing and next-generation sequencing has complicated the diagnostic odyssey for many families in the pediatric setting. While more comprehensive genetic testing promises the potential of higher diagnostic yield, it also increases the likelihood of discovering uncertain or uninformative results. The American College of Medical Genetics and Genomics and the Association for Molecular Pathology advocate for the use of a five-tier classification system for variant interpretations, comprised of the following categories: benign, likely benign, pathogenic, likely pathogenic, and variant of uncertain significance (VUS) (Richards et al. 2015). VUS are genetic variants that lack sufficient evidence to indicate whether they are benign or pathogenic, and thus are not intended to inform clinical decision-making (Halverson et al. 2020). As more research is conducted on these variants, it is expected that they will either be upgraded to pathogenic or downgraded to benign. Moreover, recent studies have shown that an important percentage of all results, not merely VUS, may be reclassified, thereby emphasizing the importance of understanding the process of variant reclassification (Mersch et al. 2018; Slavin et al. 2019).

Despite the impact that VUS reclassification can have on patients’ medical management, there are currently no guidelines delineating how variant reinterpretation should be communicated between genetic laboratories, physicians, and patients. Consensus studies have suggested that laboratories and referring providers share reciprocal responsibility in monitoring variant reclassification (Chisholm et al. 2018; Richards et al. 2015), but they have not laid out clear protocols. Evidence suggests that various laboratories and genetics healthcare practitioners differ in how they view the responsibility of staying abreast of VUS reclassification (David et al. 2019). While guidelines on how to determine variant classification exist, it is known that different laboratories classify the same variants differently (Balmaña et al. 2016).

There is also inconsistency in how healthcare providers inform patients of the implications of VUS (Mighton et al. 2020). These inconsistencies may result in a proportion of patients who have a strong understanding of the uncertainty of their result while others may be confused or misinterpret the significance of a VUS. While VUS should not be used to direct medical management, research in cancer genetics has indicated that healthcare providers have inappropriately used VUS to inform decisions as consequential as those regarding prophylactic surgeries (Garcia et al. 2014; Vos et al. 2008). Relying on VUS to make such decisions indicates that patients may not understand the uncertainty of these test results. The implications of this misunderstanding are significant, as studies have reported that 15–32% of patients undergoing multigene panel genetic testing for inherited cancer syndromes will receive a VUS (Gardner et al. 2018; Laduca et al. 2014).

Currently, little is known about patients’ understanding of VUS in the pediatric genetics setting. This limited understanding of patient experience is particularly concerning considering the volume of VUS identified on chromosomal microarray (CMA), exome sequencing (ES), and other genetic tests commonly ordered for pediatric patients (Ali-Khan et al. 2009; Jez et al. 2015; Reiff et al. 2012). Existing research has primarily focused on the psychological impact that receiving an uncertain result has on patients’ parents and guardians (Desai et al. 2018; Li et al. 2019; Lipinski et al. 2006; Wilkins et al. 2016). However, there have been few studies assessing the attitudes and values of pediatric patients’ parents and guardians regarding the variant reclassification process. To address this knowledge gap, we conducted a qualitative study in which we interviewed parents and guardians of children who have received a VUS from genetic testing through either the neurogenetics or developmental pediatrics clinics at Riley Hospital for Children at Indiana University Health.

Methods

Participants

We conducted a qualitative study using semi-structured interviews with parents and guardians of children who had been seen at either the pediatric neurogenetics or developmental pediatrics clinics at Riley Hospital for Children in Indianapolis, Indiana and had received a VUS from genetic testing. Participants were identified from each clinic’s patient records. This study was approved by the Indiana University Institutional Review Board, and all participants provided their informed consent prior to their inclusion in the study. Interviews were conducted between July and October 2020.

We recruited participants who had been informed of their child’s VUS at least 6 months before the time of their interview. Participants were required to speak English and be over 18 years old. In addition, the participants’ children were required to be under 18 years old at the time of their genetic testing. Patients who had a clinical diagnosis of a genetic syndrome or were explicitly counseled that their VUS results were excluded. Eligible parents were contacted by one of the researchers (AM) by telephone. They were read a study recruitment script that detailed the goals of the study. A $10 online gift card was offered as compensation for time spent participating in the interview, which was estimated to last 30 min. At this time, interested individuals stated their desire to take part in the study and scheduled an interview for a later date. Interviews were conducted over Zoom using only audio and were recorded. Participants could call into the service by phone if they preferred not to use video. Interviewees were de-identified and assigned a participant identification number. Contact and other relevant information was stored in a database created for this study using REDCap, a secure, web-based application designed to support online surveys and databases for research studies.

Instrumentation and procedures

A semi-structured interview guide (available in the Data Supplement) was designed to explore parents’ experiences before, during, and after their child was found to have a VUS. The interview guide was divided into three sections. The first section obtained background information regarding events that occurred before genetic testing was completed, such as why the parent pursued genetic testing for the patient and what healthcare providers were involved in ordering the testing. The second section inquired about any changes that parents have made based on the results of their children’s VUS results. The last section focused on the level of education and support that participants feel they have before, during, and after their children’s genetic testing. We also included demographic questions at the end.

Data analysis

The first three interviews were conducted by AM and CMEH, who is trained in qualitative interview methods. The remainder of interviews was conducted by the first author. Interviews were audio-recorded, transcribed, and de-identified. Transcripts were analyzed using grounded theory in order to determine common themes across interviews (Glaser & Strauss 1967). Three researchers (AM, CMEH, SP) coded the transcripts for categories relevant to the aim of the study. Three transcripts were coded and discussed by all three of these researchers to determine intercoder reliability. The researchers then coded overlapping portions of the remaining transcripts. Conflicts in coding were discussed until a consensus was reached. All authors considered recurrent concepts found throughout the interviews.

Results

Using grounded theory allowed for themes and patterns across participants’ experiences to be generated by the authors’ interpretive engagement with the data. In this article, we have chosen to focus on four themes that were identified in all interviews and have relevance to our study: (1) parental recall and interpretation of VUS, (2) knowledge of reclassification of VUS, (3) responsibility of reclassification, and (4) social and informational support for parents of children with VUS.

Participants

Interviewees included parents of children with a wide range of clinical indications, including developmental delay, autism spectrum disorder, epilepsy, and brain malformations. Only one father completed the interview, while the remaining 14 (93%) interviews were completed by mothers (including biological, adoptive, and foster mothers). Each participant’s child had received a VUS on ES (n = 7), CMA (n = 4), or a gene panel test specific to the patient’s clinical indication (n = 4). Genetic testing did not identify likely pathogenic or pathogenic variants for any children. Parents of 26 children were contacted regarding participation in the study. We had a response rate of 58%, interviewing 15 parents, who represented 15 different families. Interviews ranged in length from 14 min to 1 h and 9 min (average 25 min). The majority of participants (n = 10) had earned a college or postgraduate degree. Six children had previously undergone different genetic tests that had come back negative. The demographic information is further summarized in Table 1.

Table 1.

Demographic profile of participants

Participant characteristics		N (%)
Gender	Female	14 (93%)
	Male	1 (7%)
Age	Mean age (years)	39
	Range (years)	32–52
Education	Some college	3 (20%)
	Associate degree	2 (13%)
	College graduate	5 (33%)
	Postgraduate	5 (33%)
Ethnicity	Caucasian	14 (93%)
	Mixed	1 (7%)
Annual household income	Less than $24,999	1 (7%)
	$25,000 to $49,999	4 (27%)
	$50,000 to $99,999	3 (20%)
	$100,000 to $199,999	4 (27%)
	$200,000 or more	2 (13%)
	Unknown	1 (7%)
Relation to patient	Parent (biological or not specified)	13 (86%)
	Adoptive parent	1 (7%)
	Foster parent	1 (7%)
Clinic that ordered genetic test	Neurogenetics	9 (60%)
	Developmental pediatrics	5 (33%)
	NICU/Inpatient	1 (7%)
Genetic test	Exome sequencing (ES)	7 (46%)
	Chromosomal microarray (CMA)	4 (27%)
	Autism/intellectual disability panel	1 (7%)
	Epilepsy panel	2 (13%)
	Brain malformations panel	1 (7%)

A genetic counselor was involved in ordering genetic testing for all of the patients seen in pediatric neurogenetics clinic (n = 9). Within the pediatric neurogenetics clinic, they saw various physicians. One patient saw a geneticist, three patients saw a pediatric neurologist, and five patients saw a pediatric neurogeneticist. Genetic counselors disclosed results to seven of these families, and genetic counseling graduate students accompanied by a clinical supervisor disclosed results to the remaining two.

Of the six children seen in the developmental pediatrics clinic, one had genetic testing ordered by a geneticist, one by a developmental pediatrician, and four by a developmental pediatrician who has also been trained as a genetic counselor. Five of the patients had genetic testing ordered during outpatient appointments, while one patient had testing ordered while inpatient. This patient followed with developmental pediatrics once discharged from the hospital. A genetic counselor disclosed results to five of these families, and the developmental pediatrician with formal genetic counseling training disclosed results to the other.

Parental recall and interpretation of VUS

The majority of participants (n = 10, 67%) demonstrated a clear understanding of the uncertain nature of their child’s VUS. When asked to describe what type of results their children had received, many interviewees communicated that the clinical significance of the test results could not be definitively ascertained:

We’re not sure the impact. We’re not sure what that means. We’re not sure what other kids are like with this. We’re not sure if anything that he’s going through is actually linked to this (participant 1).

There’s just not a whole lot to be known about it yet. So, it was something that they couldn’t really say, “Okay, well, you know, this is the reason for everything going on.” But it did kind of give us at least something to say, “Okay, well, he has this genetic defect, and it could possibly be the reason for his issues” (participant 15).

The remaining participants (n = 5, 33%) could not articulate the uncertainty of their child’s genetic test result. Instead, some stated that the test result explained their child’s symptoms or that it could be used to predict what symptoms their child will have in the future. One parent explained that they had done additional research “to see what the long-term effects of it [are] going to be” (participant 2). Another parent believed that the genetic testing had confirmed a diagnosis of an autosomal recessive condition in the proband (participant 4). Further, when asked what type of result was identified, some interviewees contended that their child’s testing did not identify any genetic variants, or that it had come back negative.

There was absolutely no findings of any genetic mutations, or basically there was just no findings (participant 9).

Knowledge of reclassification of VUS

Eight participants (53%) were familiar with the concept of variant reclassification. That is, they understood that the standing interpretation of the patient’s VUS could change in the future. Individuals who had prior knowledge of reclassification expressed an understanding that more research and data are needed to reclassify a VUS:

We’re not looking for more genetic answers right now, just simply because I mean, based on the knowledge and information that the medical community has about this gene, we’ve kind of exhausted our answers. So now it’s just waiting for the science to catch up with the test results (participant 7).

I remember they told me that every year or so they can run it through a database to see if there’s any new information about any other kids who’ve had the same kind of issues (participant 13).

Two participant responses appeared to indicate that the ordering provider was currently researching or had already re-examined, the VUS in order to determine whether the classification had been updated:

We are pursuing them, re-analyzing her whole exome sequencing data since it’s been a couple of years now to see if the uncertain significant results […] mean anything now since they’ve gathered more data (participant 3).

They just kind of basically said that there wasn’t any other information in the genetic database that matched what [the patient] came back with. So let’s check it out next year. And then when we went back to the next one, there still wasn’t any, so we’re still just kind of like, “Oh, let’s see if there’s any more by this December” (participant 6).

All eight interviewees who were aware of the possibility for variant reclassification also demonstrated an understanding of VUS in general. Seven of these eight participants recalled receiving pretest counseling.

The remaining seven participants (47%) stated that they were not aware that VUS could be reclassified. Of these seven interviewees, only three recalled receiving pretest counseling.

Responsibility of reclassification

Two themes emerged when participants were asked whose responsibility they felt it was to stay apprised of whether their children’s test results are reclassified. For seven (47%), the responsibility belonged to their child’s medical provider (neurologists, geneticists, pediatricians, genetic counselors, and their respective practices).

I guess if it was reclassified, I think that whoever has the case file would need to at least notify me, I guess […] because I wouldn’t know if it was reclassified. I wouldn’t know if there was new testing being done (participant 9).

I think it would be hard for us as parents to [keep] track of that, so I guess I would say maybe genetics [is responsible] (participant 4).

Six of the seven individuals who assigned responsibility to medical providers had not previously been aware of variant reclassification. The remaining eight interviewees (53%) stated that they felt it was a responsibility shared between the parent and the child’s medical provider:

I do think that it is my job as the mom to be asking the doctors to look back into things. But I would also expect that if there were any big changes, I would hear from a genetic counselor before our yearly visit with the geneticist (participant 1).

I think it’s a joint effort. If I don’t hear something in a while, then I should probably give a phone call and be like, “Hey, just checking in.” But then at the same time, if something does change, I think it’s the doctor’s responsibility to, or at least the office’s responsibility to reach out and say, “Hey, we think we’ve got some information for you.” So I think it’s a mutual responsibility (participant 7).

Out of the eight interviewees who answered that following up on reclassifications was a joint responsibility, seven knew about variant reclassification before participating in our study.

Social and informational support for parents of children with VUS

When asked whether they had joined a support group since receiving their child’s VUS, eight (53%) interviewees disclosed that they had not done so. Of these eight, only one individual had known of a support group and nonetheless chosen not to participate. This interviewee stated that she did not join this group because there were very few members, due to the group’s highly specific focus, and she therefore believed it would be of little use to her. The other individuals who did not belong to support groups stated that they were not familiar with any relevant groups.

Seven participants had joined at least one support group following their child’s genetic testing. All but one of these participants described their support group as designed for individuals with similar symptoms (phenotype-based), as opposed to being designed for families who had received similar genetic test results (genotype-based). For example, some of the participants were involved in support groups for people who have children with autism spectrum disorder or epilepsy. The families in these groups are all raising children with similar clinical features, but not necessarily with the same genetic variant. Participants relied on these groups for support in understanding their child’s functional needs.

The majority of participants (n = 10) indicated that they would be interested in a support group specifically for individuals with variants of uncertain significance. Many individuals expressed that belonging to a support group would help them feel less isolated while they deal emotionally with the uncertainty of their child’s condition:

The knowledge that you’re not alone, because so many times when you’re doing genetic testing, it can truly feel like you are the only one out there. I mean, you can feel so isolated. Because I know in the beginning, we kind of felt that way. And still our son does not fit in any category. I mean, again, I’m a parent that has a kiddo that has a diagnosed genetic condition. [My other child] has Down syndrome. I know what it’s like to have that community behind you to say, “yes, we understand this, you know, we’ve gone through this, we get this.” I don’t have that for [patient]. So [...] it can be very isolating, not having a support group (participant 7).

Participants also recognized that a support group could serve as a source of information regarding specific VUS:

I would just be really interested to hear what other resources other parents are using and things that they’re finding very helpful. Just because I know navigating therapies and insurance, especially when there’s not a solid, solid, solid diagnosis is difficult. Schools tend to have a harder time recognizing things. I just feel like hearing what works really well for other people would take some time off my plate because I would know what to try and what to do. So that would be very helpful for me (participant 1).

Discussion

The results of this study provide novel insight into how parents of children who receive VUS in pediatric neurology or developmental pediatric clinics interpret their child’s test results. Our study explored parental understanding of uncertain test results, attitudes toward variant reclassification, and the need for additional social and informational support. Most interviewees were able to articulate clearly the principle of uncertainty surrounding their child’s VUS. This is consistent with previous research on parental understanding of VUS (Kiedrowski et al. 2016; Rosell et al. 2016). However, the fact that several participants could not accurately recount the uncertain nature of their child’s test result is concerning. With the increasing incidence of discovering VUS due to advances in genetic testing technology (Mighton et al. 2020), it is critical that genetics providers work to increase patient understanding of uncertain genetic test results. It follows that there may be a need for continued relationships between families and genetic counselors to allow for ongoing discourse about the current interpretations of patients’ VUS.

Our findings suggest discrepancies in parental understanding of variant reclassification. Notably, some interviewees who expressed awareness of the uncertainty of their child’s test result stated that they were previously unaware that VUS can be reclassified. That is, they understood that the child’s result was indeterminate but did not know that it had the potential to be upgraded or downgraded. This combination of answers suggests a disconnect: some parents acknowledged the uncertainty of a VUS but did not grasp that the purpose of being informed of a VUS was due to its potential to provide more information in the future. By definition, a VUS exists to be reclassified (Matthijs et al. 2016). Genetics providers must include a conversation on the potential for a VUS to be downgraded to a benign variant, or — although less likely — upgraded to a pathogenic variant (Mersch et al. 2018; Slavin et al. 2019). With just over half of participants indicating prior knowledge of the potential for reclassification, it is evident that not all patients are receiving the education needed to comprehend the implications of VUS fully.

Logically, it follows that we found discrepancies when discussing whom participants viewed as responsible for staying apprised of variant reclassification. If individuals are not aware of the potential for reclassification, it is unreasonable for laboratories or genetics providers to expect them to initiate the conversation regarding whether their child’s VUS has been reclassified. Our data demonstrate this point: Nearly all participants who did not previously know about reclassification shared the sentiment that this responsibility belongs to the healthcare providers alone. In contrast, most individuals who were aware of variant reclassification articulated that monitoring variant classification is a mutual responsibility between providers and themselves. Moreover, none believed responsibility lay solely with the patients or their guardians. This finding supports the notion that patients expect their healthcare providers to play an active role in informing patients of VUS reclassification (Solomon et al. 2017). Despite patients’ expectations, the structure of our current healthcare system is not equipped to assume this responsibility. Staying updated on variant reclassification and informing patients of these changes would likely occur outside of the clinical setting and be non-billable. This presents a challenge for our healthcare system to accommodate patients’ requests.

Additionally, our data emphasize the importance of pretest genetic counseling. Participants who recalled having pretest counseling were more likely to be familiar with the reclassification process than those who did not remember receiving pretest counseling. This suggests that pretest counseling may have an important impact on how parents understand and interpret their children’s VUS. Implementing guidelines on pretest counseling would benefit parents of individuals who are undergoing genetic testing (Kiedrowski et al. 2016; Semaka et al. 2013; Solomon et al. 2017). While many providers engage patients in pretest counseling conversations, the ways in which VUS are discussed are variable (Medendorp et al. 2019). Studies have suggested that genetic counselors are in favor of developing practice guidelines on pretest counseling regarding VUS to establish consistency across the profession (Medendorp et al. 2019; Mighton et al. 2020). However, such guidelines are still missing.

We found that many participants felt that their child’s having a VUS, versus a pathogenic variant, made it more difficult to find adequate support. Our findings are consistent with previous research documenting a lack of sufficient social and educational support for parents whose children have received VUS (Wilkins et al. 2016). Participants shared feelings of isolation, stemming from their child’s VUS result. While some participants had found support from phenotype-based support groups, the majority of interviewees expressed an interest in a genotype-based support group. Support groups created for parents of children with the same genetic variants would provide a community for families who are struggling with uncertainty and make them feel less alone in the midst of an otherwise very isolating experience (Plumridge et al. 2012). This model of support groups would also allow members to collaborate in their efforts to attend to reclassification. Similarly, support groups would provide a forum for parents of children with VUS to educate and learn from each other. As demonstrated in this study, interpretation of VUS is complicated. Belonging to a support group would allow for parents of children with VUS to stay better updated on variant reclassification and interpretation than they could on their own.

Study limitations

While this study provides novel insight into how parents understand uncertain results and the reclassification process, it has certain limitations. Recruitment was limited to two clinics within the same healthcare system. Although this helped ensure consistency across participants, our results may not be generalizable to all parents whose children have received VUS in similar clinics at other institutions. Another limitation is that our study relies on participants to recall conversations with genetic counselors and physicians that took place months to years prior. It is possible that participants may have forgotten details of these conversations, such as discussions on the meaning of uncertain results, before participating in this study. However, this potential recall bias is important to recognize, as individuals often wait years between receiving VUS and that variant’s reclassification (Halverson et al. 2020). Future studies should explore patient understanding of variant reclassification and the need for additional social and informational support in a wider range of clinics and specialties. Other research should work to create standardized pretest counseling guidelines regarding uncertain genetic test results.

Authors’ contributions

Authors Amy Margolin, Sandra K. Prucka, and Colin M. E. Halverson confirm that they had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All of the authors gave final approval of this version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

University School of Medicine Genetic Counseling Graduate Program.

Not applicable.