Mothers' appreciation of chromosomal microarray analysis for autism spectrum disorder.

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Journal for Specialists in Pediatric Nursing

ORIGINAL ARTICLE

Mothers’ appreciation of chromosomal microarray analysis for autism spectrum disorder Ellen Giarelli and Marian Reiff Ellen Giarelli, EdD, RN, CRNP, is an Associate Professor, College of Nursing and Health Professions, Doctoral Nursing Program, Drexel University; and Marian Reiff, PhD, MSc, is a Research Associate, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Search terms Autism spectrum disorder, chromosomal microarray analysis, mothers, thematic analysis. Author contact [email protected], with a copy to the Editor: [email protected] Disclosure: Both authors do not have any ﬁnancial interest in the content of the manuscript, or conﬂict of interest of any kind. Funding: This study was funded by the NIH/National Human Genome Research Institute R21HG006560: The impact of uncertainty in Genome-Wide Testing for Autism Spectrum Disorders (PI, Marian Reiff).

Abstract Purpose. The aim of this study was to examine mothers’ experiences with chromosomal microarray analysis (CMA) for a child with autism spectrum disorder (ASD). Design and Methods. This is a descriptive qualitative study using thematic content analysis of in-depth interview with 48 mothers of children who had genetic testing for ASD. Results. The principal theme, “something is missing,” included missing knowledge about genetics, information on use of the results, explanations of the relevance to the diagnosis, and relevance to life-long care. Two subordinate themes were (a) disappreciation of the helpfulness of scientific information to explain the diagnosis, and (b) returning to personal experience for interpretation. Practice Implications. The test “appreciated” in value when results could be linked to the phenotype.

First Received January 18, 2015; Revision received May 6, 2015; Accepted for publication May 11, 2015. doi: 10.1111/jspn.12121

Autism spectrum disorder (ASD) is one of the most common developmental disorders in children, with a rising prevalence of approximately 1% based on a population of 8-year-old children monitored in 11 geographic areas in the United States (Centers for Disease Control and Prevention, 2009, 2014). ASDs are a group of neurodevelopmental conditions that are referred to as pervasive because they affect every aspect of a person’s life. According to the revised Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 2013), anyone diagnosed with one of the four pervasive developmental disorders from DSM-IV should still meet the criteria for ASD in DSM-V or another, more accurate DSM-V diagnosis. The four disorders are autism, Asperger’s syndrome, childhood disintegrative disorder, and pervasive developmental disability—not otherwise specified. Often, terms 244

“autism” and ASD” are used interchangeably, but this is not accurate. Autism is only one of the disorders included in ASD. Furthermore, ASD is one of a number of pervasive developmental disabilities (American Psychiatric Association, 2013). ASD is characterized by atypical development in socialization and communication, and repetitive stereotypical behavioral patterns (American Psychiatric Association, 2013). A diagnosis of ASD is based primarily on reports from parents and observations of behavior by diagnosticians during a comprehensive exam. There are no biomarkers used in clinical diagnostic testing at this time, therefore the diagnosis relies on systematic clinical observations by trained specialists in developmental pediatrics, psychiatry, or clinical psychology (Walsh, Elsabbagh, Bolton, & Singh, 2011). A diagnosis that is based on clinical assessment of cognitive and social features is Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.

E. Giarelli and M. Reiff

Mothers’ Appreciation of Chromosomal Microarray Analysis for Autism Spectrum Disorder

attempted before the age of 2.5 years and can be achieved in severe cases. However, the mean age of diagnosis of ASD is approximately 5.7 years among the surveillance sample monitored by the CDC (Shattuck et al., 2009). Patterns of symptoms and multiple cases across generations within families contribute to the etiological theory that ASD is a genetic disorder, or has a significant genetic component (Carter & Scherer, 2013; Schaefer & Mendelsohn, 2013). Evidence points to a complex etiology involving genetic, epigenetic, and environmental factors (Caronna, Milunsky, & Tager-Flusberg, 2008; Persico & Bourgeron, 2006). These interactions of all contributions are still not fully understood. The earliest twin studies reported an apparent higher incidence of ASD in twin siblings. By the year 2009, there were five epidemiologic studies with twin samples in which at least one autistic proband was described and all had relatively small samples (less than 50 pairs) (Folstein & Rutter, 1977; Ritvo, Freeman, Mason-Brothers, Mo, & Ritvo, 1985; Sousa et al., 2009; Steffenburg et al., 1989; Taniai, Nishiyama, Miyachi, Imaeda, & Sumi, 2008). Among these studies, concordance in monozygotic (MZ) twins ranged from 36% to 95%, and for dizygotic (DZ) twin, concordance ranged from 0% to 23%. Rosenberg and colleagues (2009) studied patterns of ASD inheritance and other features in twin pairs by zygosity, sex, and specific ASD diagnosis. After a cross-sectional study of 277 twin pairs, they reported that pairwise ASD concordance was 31% for DZ and 88% for MZ twins (Rosenberg et al., 2009). Rosenberg reported that male and female MZ twins were 100% and 86% concordant, respectively, and affected DZ twins had an earlier age of onset (Rosenberg et al., 2009). These early twin studies contributed to the evolving theory that ASD has a genetic etiology. Additionally, ASD occurs about four times more often in boys than girls (Giarelli et al., 2010); therefore, the greatest risk factor for ASD is being male. Several recent studies provided evidence that advanced age of parents at the time of conception (fathers in particular) is associated with increased ASD risk (Cukier et al., 2014; Grether, Anderson, Croen, Smith, & Windham, 2009). Current estimates are that approximately 20% of autism cases can be explained by genetic abnormalities (Schaefer & Mendelsohn, 2013). Submicroscopic abnormalities detected by chromosomal microarray include copy number variants (CNVs) at 16p11.2, 15q11-13, and 22q11.2 (Carter & Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.

Scherer, 2013). Contemporary genetics research aims to identify risk factors and biomarkers associated with various phenotypes (Veatch, Veenstra-VanderWeele, Potter, Pericak-Vance, & Haines, 2014), as well as environmental influences that contribute to the etiology. An estimated 5% to 10% of cases of ASD are syndromic. Fombonne (2003) stated that a total of 10% to 20% of cases of ASD is due to known medical conditions involving chromosomal imbalances, genetic disorders, and environmental factors (valproate and rubella) (Alsdorf & Wyszynski, 2005). The other cases remain unexplained. Among these syndromes are fragile X syndrome, Rett syndrome, tuberous sclerosis, Smith–Magenis syndrome (Laje et al., 2010), Angelman syndrome and Prada–Willi syndrome (Nurmi et al., 2001), Smith– Lemli–Opitz syndrome (Opitz, Penchaszadeh, Holt, Spano, & Smith, 1994), velocardiofacial syndrome (Shprintzen, Wang, Goldberg, & Marion, 1985), and others. Autism might also coexist with other chromosomal abnormalities and single-gene disorders. For example, a chromosomal condition involving duplication of regions on 15q (tetrasomy15q11q13) is associated with autism (Battaglia & Carey, 2006). In addition, specific gene mutations that are causal loci have been identified on chromosomes 2, 3, 7, 15, 22, and X (Giarelli, 2013; Rutter & Thapar, 2015). Purpose of genetic testing in individuals with ASD

A genetic evaluation can determine whether an individual with ASD has “non-syndromic” or “syndromic” ASD, which has implications for clinical management of specific medical features associated with the detected genetic abnormality, and can be helpful in providing prognostic information and family counseling (Gurrieri, 2012). The diagnosis of ASD is based on developmental and behavioral assessments, and not on clinical genetic testing. Genetic testing is used to determine a possible etiology in cases where ASD has been diagnosed. An etiological diagnosis can help to determine whether the ASD is related to a genetic abnormality (Carter & Scherer, 2013; Schaefer & Mendelsohn, 2013; Veatch et al., 2014; Veenstra-VanderWeele, Christian, & Cook, 2004). In these cases, genetic information may be used to provide prognostic information (Giarelli, 2013). Depending on the cause, associated medical risks may be identified and guide screening or medical interventions to prevent comorbid conditions 245


(Schaefer & Mendelsohn, 2013). Genetic information can inform recurrence risk counseling for parents who may be considering having another child (Shen, Lincoln, & Miller, 2014), and may also help to identify younger siblings at risk of ASD, and to initiate early interventions (Miller et al., 2010; Shen, 2010; Shen et al., 2014). A causal genetic explanation can be helpful for some parents in alleviating self-blame and feeling empowered to obtain support, whereas others may feel burdened by this knowledge or have difficulty understanding the information (Reiff et al., 2012). An early diagnosis of ASD leads to early treatment, which provides the best outcomes for children and families (Agency for Health Care Research and Quality, 2011). Moreover, identification of an underlying genetic etiology can be useful for medical management and estimating the recurrence risk in the family (Coulter et al., 2011; Heil & Schaaf, 2013; Narcisa et al., 2012). Genetic/genomic tests that can be used at any age are of high interest to healthcare professionals and parents. One such test is chromosomal microarray analysis (CMA; Classen et al., 2013; Ng et al., 2010). Genetic testing guidelines: CMA

Current clinical guidelines recommend CMA as a first-line test for children with ASD, developmental delay, and multiple congenital abnormalities (Antonanzas et al., 2009; Fernandez et al., 2014; Manning & Hudgins, 2010; Miller, Ahern, Ogilvie, Giacomini, & Schwartz, 2005; Shen, 2010). This technology is used to scan the entire genome to detect CNVs, which are more common in individuals with ASD than in controls and may also be associated with other neurodevelopmental disorders (Carter & Scherer, 2013). Results of CMA fall into three broad categories: (a) pathogenic, a clearly abnormal pattern indicating the presence of a deletion or duplication in a region of the genome that is known to cause pathology; (b) negative, or a normal pattern, with no potentially pathogenic variants and no etiological diagnosis; and (c) variant of unknown significance (VUS) pattern. However, many variants (base pair deletions and duplications) are identified that have unknown clinical significance (Kohane, Masys, & Altman, 2006) because they are newly identified or there is incomplete data on the genes in the region. Such variants can occur in approximately 10% of those tested, and can vary across testing facilities (Gargis et al., 2012). In the case of VUS, clinicians offer CMA to parents for the 246


purpose of clarifying the genetic etiology by examining if there is an inheritance pattern, and if the variant is pathological or benign (Mefford et al., 2008). In essence, CMA might be considered another screening tool because of the potential to identify genetic variants of unknown clinical significance. Sometimes, the variation is as small as a single nucleotide base, and there is no sure way to associate that variation with the symptoms in the individual. CMA might also be seen as exploratory because there remains a high potential for uncertainty in the interpretation of results, and in the implications of results for the children tested and for their parents (Ali-Khan, Daar, Shuman, Ray, & Scherer, 2009; Darilek et al., 2008; Tabor & Cho, 2007). In addition to VUS findings, genomic technologies such as CMA can identify incidental or secondary findings (i.e., clinically relevant genetic variants unrelated to the reason for testing), including predisposition to late onset conditions. Incidental findings are rare and have been detected in approximately 1% of individuals undergoing CMA testing (Mulchandani, Conlin, Thiel, & Spinner, 2012). VUS and incidental findings can present challenges for families, and pre- and posttest counseling are recommended to assist families in understanding the results and their implications (Abdul-Karim et al., 2013; Committee on Bioethics; Committee on Genetics; and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee, 2013; Gutmann et al., 2013; Heil & Schaaf, 2013; Miller et al., 2010; Selkirk et al., 2009). Clinical guidelines recommend that pretest counseling should prepare patients and families for the potential that incidental or secondary findings might be detected (Green et al., 2013; Gutmann et al., 2013; Kearney, Thorland, Brown, Quintero-Rivera, & South, 2011; Manning & Hudgins, 2010). Ethical concerns have been raised about the potential harm associated with disclosing incidental findings; however, it is recommended that families are informed about incidental findings in children for conditions with proven clinical management that minimizes the risk of future adverse outcomes (Green et al., 2013). It is the hope that once there is a clear understanding of the genetics of ASD, the genetics can be associated with the phenotype and used in a way to predict incidence and severity of symptoms. Parental responses to genetic test results. Diagnostic genetic testing of children can be stressful Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.



for parents because of uncertainty surrounding the diagnosis and prognosis for the individual tested (Stewart & Mishel, 2000; Timmermans & Buchbinder, 2010; Tluczek, Chevalier McKechnie, & Lynam, 2010; Tluczek, Orland, & Cavanagh, 2011). Parents of children with rare disorders have been found to have high levels of perceived uncertainty due to limited prognostic information and variability of the clinical phenotypes (Lipinski, Lipinski, Biesecker, & Biesecker, 2006). Research has found that although attribution of genetic causation can alleviate parental self-blame for being in some way responsible for their child’s condition (Lenhard, Breitenbach, Ebert, Schindelhauer-Deutscher, & Henn, 2005; Makela, Birch, Friedman, & Marra, 2009), parents’ feelings of guilt or blame may also be increased by the knowledge that they, or their spouse, have passed on a genetic condition to their child. Knowing the genetic causation of a disorder can also contribute to parents’ anxiety by increasing the perceived seriousness of a disorder and the concern that siblings and children might develop the same problem (McMahon, Baty, & Botkin, 2006; Phelan, 2005; Phelan, Cruz-Rojas, & Reiff, 2002). Although not knowing a definite diagnosis for a child’s disorder is stressful, lack of this information may provide some parents with psychological benefits such as avoiding labels, and allowing room for optimism (Rosenthal, Biesecker, & Biesecker, 2001; Whitmarsh, Davis, Skinner, & Bailey, 2007). In Biesecker and Erby’s (2008) review of evidencebased theoretical models, they suggested that the level of stress that families experienced was related, in part, to the severity of the child’s disorder (Biesecker & Erby, 2008). Other studies of parents of children with ASD have found that parental stress and coping was associated with the severity of the child’s symptoms (phenotype) (Duarte, Bordin, Yazigi, & Mooney, 2005; Estes et al., 2009) as well as other factors including feelings of uncertainty, sense of control, and hope (Hastings et al., 2005; Higgins, Bailey, & Pearce, 2005). In two separate studies, researchers reported that parents of children with ASD found value in genetic testing for alleviating guilt, promoting awareness, tailoring interventions, and informing family planning (Chen, Xu, Huang, & Dhar, 2013; Trottier et al., 2013). In summary, ASD is one of the most common serious developmental disorders in children, with the prevalence approaching 1% of the U.S. population. Families are offered CMA, yet little is known about the mothers’ experiences with this test and their perceptions of the social and psychological Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.

impact. The specific aim of this article is to describe mothers’ experiences with CMA of their child with ASD. Results may be used by clinicians to identify ways to promote parents’ positive experiences with genetics testing and improve parents’ coping with results. DESIGN AND METHODS

For this descriptive qualitative study, the researchers applied thematic content analysis to data collected from mothers regarding their experiences with genetic testing of their child who was diagnosed with ASD. All institutional regulatory approvals were obtained prior to initiating the study. This study was part of a larger mixedmethods project that included telephone interviews followed by online surveys. This article used data from the telephone interviews of the mothers only, who were the major subset of all study participants. The larger study examined a range of difference variables involved in the use of CMA for ASD. Participants

Purposive sampling (Sandelowski, 1985; Strauss & Corbin, 1998) was used to recruit eligible participants. Respondents were invited based on their willingness to engage in in-depth discussions and on their particular expertise with CMA for ASD. This strategy attempted to ensure comparable numbers of participants in each of three CMA result categories: pathogenic, VUS, and negative. Procedures

Potential participants were identified through the databases of: (a) the cytogenetics lab of a large, urban, pediatric medical center; and (b) a private, for-profit company that provides physicians with an integrated genetic testing, counseling, and developmental screening service to aid in the clinical evaluation of children with ASD or other forms of developmental delay. The inclusion criteria for the mothers were: above 18 years of age, had a child with a diagnosis of autism or ASD who had undergone CMA, and spoke English. The age of the child at testing was not an inclusion or exclusion criterion. There were no restrictions based on race or ethnicity. Mothers were the focus of this study because they are consistently identified in the literature as more likely to be the primary caregiver. 247



Figure 1 Principal and Subordinate Themes Illustrating Mothers’ Experiences with Chromosomal Microarray Testing for Autism Spectrum Disorder. Note: CMA, chromosomal microarray analysis.

We used purposive sampling to recruit equal numbers of participants receiving each of the three types of possible CMA results (pathogenic, VUS, and negative). Our goal was to include approximately twenty participants per result type. Laboratory staff at the two sites identified children who had been tested using CMA and had a diagnosis of ASD. The laboratory staff selected all the children with pathogenic and VUS results and a sample of those with negative results to receive invitations. The result type was not known to the research staff until after the participants had consented to participate in the study and granted their permission for their result to be disclosed. Invitation letters and brochures explaining the study were sent to 232 families (143 from the hospital laboratory and 89 from the commercial laboratory). The letters included contact information and instructions to call or otherwise contact a member of the staff at the recruiting sites for additional information and to volunteer to be enrolled. Parents provided their name and demographic information to the study coordinator. Those who did not respond were telephoned by research staff to ascertain their interest in participating. We offered $25 as an incentive. A total of 57 parents (48 mothers and 9 fathers) participated in the study. This article reports data from the 48 mothers.

[America’s Inc.], Burlington, MA, USA), a software program used to manage, code, and analyze qualitative data (Bazeley, 2007). This helped us maintain an audit trail to enhance confirmability. Data were collected between October 2012 and September 2013. The investigators applied a strict process of data collection and analysis to assure scientific integrity. We searched for the comments of participants who offer conflicting viewpoints to strengthen a comprehensive description of a phenomenon. Data analysis

Data were analyzed using thematic content analysis as proposed by Boyatzis (1998). Coding and qualitative analysis occurred at two levels of complexity (Miles & Huberman, 1994; Strauss & Corbin, 1998). Level I, or line-by-line, coding was used to identify units of meaning from transcribed text. This step was followed by level II coding to raise the level of abstraction to conceptual categories and subcategories. Principal theme and conceptual categories and the subordinate themes are illustrated with a visual model (see Figure 1) (Sandelowski, 1985; Strauss & Corbin, 1998). RESULTS

Data collection

Characteristics of the sample

Data were collected by in-depth, semistructured interview. Interviews ranged from 30 to 60 min and were conducted by telephone and audiotaped. Each parent participated in one interview. We attempted to enhance the privacy during the interviewing process by reminding participants to seek an environment that was quiet and in which the interview, which was audio-recorded, would be uninterrupted. Audio tapes were transcribed, de-identified, and imported into NVIVO10 (QRS International

Sample characteristics are reported in Table 1. A total of 57 parents (48 mothers and 9 fathers) participated in the study. Details regarding the study sample are reported in Reiff et al. (in press). This article reports data from the 48 mothers. Mothers were grouped by CMA results: pathogenic; negative or VUS. The 48 mothers participated in telephone interviews from the hospital (75%, n = 36) and from the commercial genetic testing facility (25%, n = 12). The majority of the participants identified

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Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.



Table 1. Sample Sociodemographics Characteristics for Mothers and Children Demographic information

(N = 48)

Mean (SD)

Age

Mean parent age Mean child age at interview Mean child age at test Mean child age at diagnosis

41.3 (8.0) 9.3 (5.2) 7.6 (4.9) 3.9 (2.4)

Age categories Parent age

Child age (at interview)

Race

Marital status

Sex of child Test result

Time since test

Parent education

Number of children

Employment

Health insurance Source of recruitment

25–29 30–39 40–49 50 + 0–3 4–6 7–9 10–14 >15 African American White Mixed Single (1) Married (2) Divorced/separated (3) Female Male Variant (1) Abnormal (2) Normal (3) Average time since test (months) Not reported 5–12 13–18 19–24 25+ Less than high school Completed high school Some college Graduated college Postgraduate 1 2 3 4+ Employed full time Employed part time Full time homemaker Retired Student Unemployed Yes No Hospital Genetic testing facility

themselves as White (81%) and married (81%), and had some college or higher educational level. The mean age of respondents was 41.3 years (SD 8.0). The age of diagnosis ranged from 1 to 13 years. The Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.

Total number

Percentage (%)

2 21 17 8 4 16 9 11 8 6 39 3 4 39 5 9 39 15 16 17

4.2 43.8 35.4 16.7 8.3 33.3 18.8 22.9 16.7 12.5 81.3 6.3 8.3 81.3 10.4 18.8 81.3 31.3 33.3 35.4

3 23 7 4 11 4 5 11 15 13 12 19 13 4 17 6 13 1 3 8 46 2 36 12

6.3 47.9 14.6 8.3 22.9 8.3 10.4 22.9 31.3 27.1 26.0 39.6 27.1 8.3 35.4 12.5 27.1 2.1 6.3 16.7 95.8 4.2 75.0 25.0

18.4 months

children who were tested ranged from 3 to 24 years of age at the time of the study. The mean age of the child when tested was 7.6 years (SD 4.9). The time between clinical diagnosis and genetic testing 249


ranged from 0 to 179 months, and for some was many years after the child was diagnosed. The results of the CMA were equally distributed across pathogenic, negative, and VUS. From the data, we identified one principal theme with three conceptual categories and two subordinate themes that are consequences of the principal theme. They are described below. Principal theme: something is missing

Mothers of children with ASD sought information and explanations. They wanted a full understanding of the causes of their child’s disorder as well as information on how to treat and mitigate the life-long consequences. Mothers who agreed to genetic testing for their child expected that the test would provide some insight or answers to their persistent question of “why?” Test data were analyzed to reveal that some mothers experienced some measure of satisfaction from the experience when they learn the results of the genetic test. This was especially true when the CMA was abnormal (pathogenic) because these mothers were able to have their suspicions confirmed. This was not, however, a universal experience for the mothers of the children with pathogenic findings. It was not the experience for many of the mothers who received results that were “negative” or “variant of unknown significance (VUS).” The majority of the mothers who received negative and VUS results were aware that “something was missing” and consistently identified that something that they expected or sought from the testing process was not received. There were three missing items. Conceptual category: missing information about genetics. Mothers recognized the increased complexity in the nature of the puzzle of ASD. The experience of testing invariably led to mothers comparing their expectations or hopes to the end experience, that is, dissatisfaction, or equivocal explanation of the cause of the disorder. This occurred primarily because of the nature of their expectations. They seemed to have hoped that the CMA would provide the missing pieces to the puzzle and answer their questions they had of why and how it (ASD) occurred, when it started, or if there were any identifiable genetic causes. They reported their lack of knowledge about genetic concepts, but some reported that they did not receive sufficient instruction or that during counseling, they did not understand the information they received about 250


genetic concepts This included basic information on the actual test such as how it was performed and who performed it. For some mothers who received pathogenic results, the lack of accurate information on genetics was apparent. This mother’s statement was illustrative: I mean, he’s missing some chromosomes, which causes the autism and other things. It’s pretty self-explanatory the description of the genetic thing. He’s missing things and unfortunately, he has no way of getting those chromosomes at all. (Result type: VUS)

Conceptual category: missing information on use of results. Mothers wanted practical benefits from the testing. It naturally follows that they would expect the test result to contribute something to their understanding of the disorder, and, it is hoped, contribute to their child’s care. When mothers were asked if the results would be useful, one mother stated: No, there’s nothing I can change. My son has autism and that’s it. The genetic test is not going to make a difference—because he had that genetic testing, it didn’t solve any—it didn’t ease my mind or anything. It just made it worse because then it came back that he had [a defect in] chromosome 15 (Result type: Pathogenic)

To this mother, the knowledge of a genetic variant was perceived as not contributing to her ability to find a treatment for ASD, or to care for her child. Knowing the genetic variant was not useful to this parent’s understanding of the child’s symptoms (phenotype). Another mother shared this thought: They just did the testing and said we would go from there. And everything came back as normal [no genetic abnormality] so they didn’t say anything other than that. Everything was normal. We didn’t have anything to really worry about. . . . My son still has autism [long pause]. So he is not normal. (Result type: Negative [normal])

Implied is her realization that the test was not useful in helping her to understand the cause of her child’s disorder or to help plan for treatment or care. Conceptual category: missing explanations of relevance to diagnosis and life-long care. Some mothers sought an unequivocal explanation to the cause of their child’s ASD. Mothers shared that they were disappointed with the results. Such statements imply that mothers expected that the genetic test would remove uncertainty. This mother shared her Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.



feelings about the mismatch between her expectations for and the actual explanation of the relevance of test findings. I was disappointed. It’s not to say that we were hoping for a genetic answer, but we were-kind of- and so many people, professionals, have said to us, “there must be some kind of genetic component in your family that you have three.” All of our children have autism, whereas other people don’t. So we were sort of, I don’t want to even say expecting, but we were hoping maybe to get some kind of a genetic answer that could give us something to go on. We thought that there might be something genetic that was going on but nothing appeared that would have given reason for the symptoms. (Result type: Negative)

A list of all items (concepts) reported as missing by the mothers are in Box 1. Subordinate theme: disappreciation

The term appreciation was broadly understood to encompass all definitions including: regard for or showing gratitude, understanding or comprehending, recognizing worth, and elevating in stature or advancing its use. Nearly all of the mothers in this study were grateful for the opportunity to have their child tested for a genetic contributory factor. This was most conspicuous among mothers of children who had pathogenic findings. The mothers began with the hope that the science of genetics and the technology

of CMA would aid their comprehension of the complex disorder and enlighten them with regard to the etiology. However, many were disappointed, and the result was a diminished appreciation for the science and the value to them. This mother’s comment summarized the belief that there was little to be gained from testing, but it might be approved by a parent if there was little to lose (low risk). She said: I think if you’re curious and you have the money to do this and you’re not going be taking money away from other things, your vacation to Disneyland, food or anything like that, then I think it is a potential that you might find something helpful for your child, or you might also find something that could be a potential help to society as we try to figure this out. But if it’s going to cause financial stress to have this test done, then I wouldn’t necessarily recommend that you do that. (Result: VUS)

In general, this cohort of mothers was critical of the process of receiving the results. They estimated the relative value of the findings to their child and family, regardless of the actual findings (abnormal [pathogenic], normal [negative], VUS). Mothers who received abnormal or pathogenic findings acknowledged that in the future, these tests may be more useful to mothers and diagnostician, thus ultimately “appreciating” in value when the technology is able to link genetic variants to the child’s symptoms [phenotype] with a hope for treatment.

Box 1. Conceptual Categories of the Principal Theme, Something is Missing: Reports From the Mothers of What Was Missing From Their CMA Testing Experiences Missing Information About Genetics/Genomics Instructions about genetics and genomics, in general Information on the genomics of autism spectrum disorder Instruction about the testing process Pretest information on what is being tested Missing Information on Use of Results Sufficient pretest counseling on purpose of test Sufficient posttest counseling on medical use of the findings Information on relationship between genomics and child symptoms (phenotype) Missing Explanations of Relevance to Diagnosis and Life-Long Care Information on future use of test results for treatment Explanations of the relevance of the findings to the diagnosis Information on the relevance of the findings to life-long care Sincerity (questioning motives of tester “just for them”) Purpose questioning the worth of the science


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Subordinate theme: returning to personal experience for interpretation

When given test results that were normal or VUS, mothers shared that they relied on their personal knowledge, intuition, and experience to interpret the value and meaning of the test results. One mother who received normal and VUS results reported being disappointed and also stated they she “didn’t need a test result to tell me my child had the disorder. . . . I just know.” This mother shared her personal observations, stories of the experiences of other mothers, their intuitions and predilections, their opinions, and situational factors to interpret the meaning of the CMA results to their child and other members of the family. This illustrates a reliance and return to personal knowledge. It appeared to be the result of parents’ struggling to accommodate the information received from the genetic testing with what they already believed to be true. They reconciled that the test results did not add the last piece to the puzzle of their child’s diagnosis. One mother who received results that were pathogenic said, “I already know it was genetic, I just know.” Others had similar descriptions. Another mother who received a result that was equivocal (VUS) said it this way: “it doesn’t really matter what the tests say, I know what caused my child’s autism.” The lack of sufficient and complete knowledge of genetics appears to lead the mother to rely on her own experience, family history, or beliefs to make sense (interpret) the meaning of the test result. It’s very unusual, whatever it showed on the DNA, whatever they were looking for. They found something. And it totally defies the origination of it, because nobody on both sides of the families of multiple generations has any type of mental retardation or anything. They’re all normal. And my mother is going to be 83. She’s got brothers and sisters who are [ages] in their early to mid-80’s. And there are offspring—second, third generation- nobody has [genetic problems]. No mental retardation, no physical disabilities, muscular dystrophy, MS, nothing. (Result: VUS)

Some mothers, who received pathologic results continued to attribute the disorder to various nongenetic events such as: “God’s will,” nature, fate, [prenatal] carelessness, vaccines, or other exposure or environmental factor. Faced without a definitive cause, some mothers reported some relief from uncertainty. One mother who received results that were normal said: I guess in some ways there were certain things I tried to rule out, but we still don’t know the cause of the disease

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and it’s so complex, not really. If I had found something out, [that] there was a marker, I would have a direction to go in to find out what treatments are useful in kids with that specific [genetic] defect. Since I didn’t find anything out, I just continue to do things the way I’ve been doing them. (Results: Negative)

In summary, the participants identified many items that were missing from the CMA experience. Items were grouped into those actions they would have expected to be included in the testing process and explanations that they expected in order to fully understand the value of testing and the use of test results. For example, the mothers expected to be given instructions about genetics and genomics in general and specific information on the genetics of ASD. These missing pieces of information are group under the category of Missing Information about Genetics/Genomics. The expectations also fall under the categories of Missing Information on Use of Results and Missing Explanations of Relevance to Diagnosis and Life-Long Care. Examples are listed in Box 1. Figure 1 is an illustration of the basic relationship between the principal theme, something is missing and the subordinate themes of disappreciation and returning to personal experience. The subordinate themes are defined. PRACTICE IMPLICATIONS/DISCUSSION

A genetic diagnosis can be beneficial for the medical care of the patient and for determining recurrence risk (Coulter et al., 2011; Miller et al., 2005; Shen, 2010). However, seeking genetic testing as part of the diagnostic process for ASD can have mixed outcomes for the mothers in that the results may not provide them with the resolution to the question of the cause of their child’s disorder. Information that adds to the etiological explanation can provide psychological benefits for mothers for whom the test results are positive. Presumably, such information might decrease levels of uncertainty and anxiety, improve coping and adaptation, increase their sense of control, and relief from guilt as seen with other conditions (Lenhard et al., 2005; Lipinski et al., 2006; Makela et al., 2009). Analyses of qualitative interviews with our sample of mothers of children with ASD revealed a more complex response to the report of the CMA results as well as disappointment that the results did not provide answers to troubling and ongoing questions about cause, prognosis, and treatment. This may be due to mothers’ misunderstandings of results as presented to them, or the inadequacies of Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.



counseling services provided after the test results were reported. These factors have been noted in recent studies of CMA for ASD. For example, three reports by Reiff and colleagues (2012, 2013, 2014) included mothers and providers of children tested with CMA and findings substantiated that challenges in communicating uncertain and incidental CMA findings were associated with mother’s misunderstanding of the value of the test. Uncertain genetic diagnostic information can be a barrier to adaptation (Biesecker & Erby, 2008; Lenhard et al., 2005; Lipinski et al., 2006). This study supports work previously conducted on barriers to adoption of CMA for ASD. Parents clearly identified deficiencies (things missing) from the testing process that might pose barriers to adaption, and that if included could have helped their coping. CMA is used clinically to assist in confirming a suspected genetic etiology for patients with ASD, despite the potential for VUS findings (Manning & Hudgins, 2010; Miller et al., 2005; Shen, 2010). Therefore, clinicians must understand the purpose and limitations of the test, along with the understanding of the potential psychological reactions parents might have to the findings. However, as long as CMA testing produces equivocal findings and the genetics are being explored, nurses will have difficulty distinguishing clinically significant from clinically insignificant results. If nurses are uncertain of the value of the tests, their communications with mothers might reflect this uncertainty. Nurses providing care for families with a child undergoing CMA might benefit from in-depth discussions with genetic counselors before and after the family’s experiences. During such meetings, both nurses and families might jointly discuss how results might be used, including those that are ambiguous. Nurses may anticipate that parents will ask questions. One question might concern payment for tests or the costs of medical monitoring and screening for presymptomatic conditions for which a genetic risk is discovered (McGuire et al., 2013). For example, if the test is covered by the parent’s insurance plan. Another question might be if the test result will guide approaches to treatment (Aronowitz, 2009). This question is best addressed by the team composed of physician, nurse, and genetic counselor after the results are evaluated. CMA testing may produce incidental findings, which are results that are unanticipated and beyond those related to the purpose of the test. This might be especially unsettling for mothers. Nurses might anticipate this outcome and prepare the family by Journal for Specialists in Pediatric Nursing 20 (2015) 244–258 © 2015, Wiley Periodicals, Inc.

reviewing the literature and having available a list of services for psychological counseling and medical or other referral options. This advance preparation might convey to the family that such incidental findings are, to some extent, anticipated and can be managed. Genetic specialists have encountered these findings and can confer with nurses prior to discussing the results with families. The principal concerns reported by providers regarding sharing incidental findings include the potential to cause psychological harm in recipients and the need for creating formal disclosure guidelines (Downing, Williams, Daack-Hirsch, Driessnack, & Simon, 2012; Reiff et al., 2014). Clarity of the purpose of the test

Nurses might recall and share with parents that according to the guidelines for the use of genetic test results in pediatric populations, there are risks and benefits to knowing a genetic risk for a disorder in a child (Abdul-Karim et al., 2013). However, more work is needed to implement these recommendations. In 2012, Downing and colleagues (2012) called for more interdisciplinary communication, maintaining contact with families, and creating a centralized database to interpret the meaning of variants of unknown significance. The explanations, information, and activities reported as missing by the mothers may have been actually provided during the CMA process according to clinical guidelines by the clinician during the counseling process. Mothers’ experiences with the process, however, led us to imply that there may need to be a review of genetic counseling content and process to assure that mothers comprehend all the information that is shared. Pediatric nurses have experienced providing supportive care for both child and families. This unique expertise might be integrated with the counseling process to optimize therapeutic outcomes of CMA. Occasionally, when genetic testing is offered, parents may not be certain the testing process is part of clinical practice of a research protocol. It is imperative that nurse confirm the purpose of the testing and confirm that parents clearly understand the difference between a component of a diagnostic work-up and the exploration of potential etiological factors. Nurses should tell parents that a presidential committee has recommended that patients and research participants are prepared and educated regarding the possibility if incidental findings in genomic tests like CMA and whole genome/exome sequencing (Gutmann et al., 2013). 253


Finally, we examined the mother’s comments for apparent difference based on age and found nothing to report. The age of the mother did not emerge as a factor in their remarks, nor did the sex of the child. The age range of the child who was tested was wide and the sample was too small to cluster by age group. Thus, we focused our analyses on the experiences of the mothers. We believe a future study with a larger sample (if obtainable) might allow such cluster analyses and might be used to generate algorithms of care/counseling. Limitations

The perspectives of fathers were not included in the report. Research focusing on maternal experiences is justified because of the facts that the majority of subjects were female, and historically, women have been largely responsible for child-rearing and therefore would arguably be the mother most affected by the diagnosis of a chronic disability in their child (Altiere & von Kluge, 2009). However, we acknowledge that fathers play an important role in raising children with ASD. We caution that the findings from this study represent the perceptions of the mothers only, and therefore cannot be interpreted to be relevant for fathers. The purposive sample provided three groups of comparable size in order to assess utility across different result types; however, the study was limited by a fairly low response rate. The reasons for nonparticipation are unknown, but it is likely that some invitations were not received because of outof-date contact information. There may have been some bias in the sample, for example if parents of children with more severe illness were less likely to participate, but this was not assessed.

How might this information affect nursing practice?

CMA results have psychosocial implications for mothers. Mothers reported that they required more information and guidance after testing. The testing process can be stressful because of the uncertainty surrounding the diagnosis and prognosis for the child (Stewart & Mishel, 2000; Timmermans & Buchbinder, 2010). Uncertainty may be confusing to mothers and might lead to adverse psychosocial outcomes (Almqvist, Brinkman, Wiggins, Hayden, & Canadian Collaborative Study of Predictive Testing, 2003;

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Lenhard et al., 2005; Lipinski et al., 2006). Uncertainty and parental stress are components of the larger experience of selecting genetic testing as part of the diagnosis evaluation of the child with ASD or suspected of having ASD. It is possible that the popular use of the image of a puzzle to illustrate ASD has become a fundamental expectation for mothers, such that they expect that there will always be missing pieces in the diagnostic picture of their child’s disorder and they will need to continue to seek answers to this enigma. CMA has complex ethical and public health implications, including the difficulty clinicians have distinguishing the clinical significance of findings when the child with ASD has “normal” genetics or finding of unknown significance. In all cases, there is a need for counseling pre- and postgenetic testing to prepare the parents for, and then explain, ambiguous results. Clinicians might anticipate that mothers who agree to CMA for their child may experience a lack of clarity regarding the purpose and the ultimate value of testing. Nurses should aim to find suitable vocabulary to explain to mothers how to balance information about “that which is known” and “that which may never be known.” Nurses must also expect that mothers will have some realistic and some unrealistic expectations regarding the applicability and clinical usefulness of test results, and assist mothers to find ways to use results in a way that is life-affirming and realistic. References Abdul-Karim, R., Berkman, B. E., Wendler, D., Rid, A., Khan, J., Badgett, T., & Hull, S. C. (2013). Disclosure of incidental findings from next-generation sequencing in pediatric genomic research. Pediatrics, 131(3), 564–571. Agency for Health Care Research and Quality. (2011). Therapies for children with autism spectrum disorders: A review of the research for parents and caregivers (pp. 1–16). Bethesda, MD: Author. Retrieved from http://www .effectivehealthcare.ahrq.gov/ehc/index.cfm/search -for-guides-reviews-and-reports/?pageAction =displayProduct&productID=1974 Ali-Khan, S. E., Daar, A. S., Shuman, C., Ray, P. N., & Scherer, S. W. (2009). Whole genome scanning: Resolving clinical diagnosis and management amidst complex data. Pediatric Research, 66(4), 357–363. Almqvist, E. W., Brinkman, R. R., Wiggins, S., Hayden, M. R., & Canadian Collaborative Study of Predictive Testing. (2003). Psychological consequences and predictors of




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Next Generation Sequencing Mitochondrial DNA Analysis in Autism Spectrum Disorder.

Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis.

Mothers' expressed emotion towards children with autism spectrum disorder and their siblings.

Substantial lifelong cost of autism spectrum disorder.

High prevalence of pathologic copy number variants detected by chromosomal microarray in Swiss-Italian children with autism spectrum disorders.

Sulforaphane treatment of autism spectrum disorder (ASD).

Autism spectrum disorder: importance of audiology.

What Do Parents Think about Chromosomal Microarray Testing? A Qualitative Report from Parents of Children with Autism Spectrum Disorders.

Problem-solving skills training for mothers of children recently diagnosed with autism spectrum disorder: A pilot feasibility study.

Incontinence in children with autism spectrum disorder.

Cerebro-cerebellar circuits in autism spectrum disorder.

Empathic Embarrassment Accuracy in Autism Spectrum Disorder.