Chromosomal microarray impacts clinical management

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1 Clin Genet 2014: 85: Printed in Singapore. All rights reserved Original Article 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: /cge Chromosomal microarray impacts clinical management Riggs E.R., Wain K.E., Riethmaier D., Smith-Packard B., Faucett W.A., Hoppman N., Thorland E.C., Patel V.C., Miller D.T. Chromosomal microarray impacts clinical management. Clin Genet 2014: 85: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2013 Chromosomal microarray analysis (CMA) is standard of care, first-tier clinical testing for detection of genomic copy number variation among patients with developmental disabilities. Although diagnostic yield is higher than traditional cytogenetic testing, management impact has not been well studied. We surveyed genetic services providers regarding CMA ordering practices and perceptions about reimbursement. Lack of insurance coverage because of perceived lack of clinical utility was cited among the most frequent reasons why CMA was not ordered when warranted. We compiled a list of genomic regions where haploinsufficiency or triplosensitivity cause genetic conditions with documented management recommendations, estimating that at least 146 conditions potentially diagnosable by CMA testing have published literature supporting specific clinical management implications. Comparison with an existing clinical CMA database to determine the proportion of cases involving these regions showed that CMA diagnoses associated with such recommendations are found in approximately 7% of all cases (n = 28,526). We conclude that CMA impacts clinical management at a rate similar to other genetic tests for which insurance coverage is more readily approved. The information presented here can be used to address barriers that continue to contribute to inequities in patient access and care in regard to CMA testing. Conflictofinterest D. R. is a full-time employee of GeneDx, a for-profit company that performs chromosomal microarray (CMA) testing. W. A. F. is the recipient of an NIH-funded grant to study CMA testing in the prenatal setting. Other authors have no financial disclosures and report no conflicts of interest relevant to this article. E.R. Riggs a, K.E. Wain b, D. Riethmaier c, B. Smith-Packard d, W.A. Faucett d, N. Hoppman b, E.C. Thorland b, V.C. Patel a and D.T. Miller e,f a Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA, b Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, USA, c GeneDx, Gaithersburg, MD, USA, d Geisinger Health System, Danville, PA USA, e Division of Genetics, and f Department of Laboratory Medicine, Children s Hospital Boston, Boston, MA, USA Key words: array comparative genomic hybridization chromosomal microarray analysis genetic testing patient care management Corresponding author: David T. Miller, MD, PhD, Division of Genetics, Children s Hospital Boston, Hunnewell 5, 300 Longwood Avenue, Boston, MA 02115, USA. Tel.: ; fax: ; david.miller2@childrens.harvard.edu Received 29 November 2012, revised and accepted for publication 18 January 2013 Genomic copy number variation (CNV) contributes to the etiologies of global developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), and multiple congenital anomalies (MCA) (1 3). Because of this, genetic evaluation has been recommended by several professional societies as a part of the standard assessment for individuals with these features when the underlying cause is unclear (4 7). Cytogenetic studies, such as karyotype and fluorescence in situ hybridization (FISH), each with diagnostic yields in the range of 2 3% (8), have historically been the evaluations of choice for this patient population. More recently, however, it has been shown that chromosomal microarray analysis (CMA) has a higher detection rate (ranging from 12% to 19%) (8 12); further, decision analysis modeling suggests that using CMA as a first-tier test prior to karyotype provides good value among this group of patients (13). Given this body of evidence, CMA has now been recommended in professional practice 147

2 Riggs et al. guidelines as a first-tier evaluation for these patient populations (1). Although the improved diagnostic yield of CMA is well documented, less data exist regarding its impact on clinical management (14). In a retrospective study of 1792 patients with non-specific DD, ID, ASDs, and/or MCA, positive CMA results generated a recommendation for clinical action in 55% of cases (15). No data on medical outcomes as a result of these management decisions were collected, but CMA results clearly influenced decisions about medical care. Additional reports have been published about other cases where CMA resulted in changes in management (16 18). Reimbursement policies for CMA vary by payer in the United States, and anecdotal reports by clinicians indicate that some patients have been denied coverage. At least a portion of these denials may be based on the idea that CMA results may not have a direct impact on clinical management, as evidenced by policy stipulations in place for certain groups (19, 20). To our knowledge, there has been neither a systematic effort to document the experiences and concerns of ordering providers nor has there been an effort to determine what proportion of results on standard CMA are actionable according to the documented clinical management recommendations. Such information could help inform decisions about CMA reimbursement by payers. Materials and methods Survey of ordering practices for chromosomal microarray Ordering practices of genetics professionals and the factors that influence these practices have not been fully explored. Members of the National Society of Genetic Counselors (NSGC) and the American College of Medical Genetics (ACMG) from 41 states and Canada completed an online survey (n = 180) regarding clinical practices around ordering of CMA. All survey results were completed between 1 June and 15 November, Survey questions can be viewed online ( monkey.com/s/8zpmpm7 for NSGC members, and for clinician ACMG members). Determining clinically actionable regions of the genome covered by CMA Among the 384 individual genes currently targeted on the International Standards for Cytogenomic Arrays (ISCA) Consortium 180K array design (21), those considered to be associated with a well-described genetic syndrome (specifically, genes that were the focus of articles within GeneReviews) were selected for review (n = 153) (Fig. 1). Additionally, genomic syndromes described within GeneReviews, DECIPHER ( and the ISCA Consortium known pathogenic list ( Fig. 1. Number of phenotypes evaluated for medical management implications. ncbi.nlm.nih.gov/dbvar/studies/nstd45/) were also included (n = 52). Overall, this resulted in a total of 235 phenotypes for review, as some genes/genomic regions were associated with more than one distinct phenotype. Forty-nine of these phenotypes were excluded as they were not considered potentially diagnosable by CMA testing (i.e. haploinsufficiency/loss of function or triplosensitivity mechanisms have not been described in association with the phenotype); this included autosomal recessive syndromes and phenotypes caused by alternative mechanisms (e.g. gain of function). Phenotypes were still considered potentially diagnosable by CMA if loss of function has been established as a mechanism but whole or partial-gene deletions have not been documented. The 186 remaining phenotypes were evaluated for evidence of clinical actionability (Table S1, Supporting information). We defined clinically actionable regions of the genome as those associated with phenotypes potentially diagnosable by CMA for which at least one of the following types of interventions would be recommended: R = referral to a specialist (at least one time) for management of potential complication(s) associated with genetic variant; D = diagnostic testing (including lab tests, echo and other imaging) indicated to evaluate possible complications that would not otherwise have been suspected; P = surgical/interventional procedure may result or be contraindicated; S = surveillance (recurrent) for potential complication(s) associated with genetic variant (could be some type of medical exam or diagnostic imaging); M = medication to treat some aspect of the condition (either to consider prescribing or medication might be contraindicated); L = lifestyle changes to mitigate some risk of the condition; and O = other. We did not include counseling about recurrence risk as an intervention because that would apply to all types of genetic test results. The diagnoses were stratified according to the level of evidence supporting clinical management recommendations for each phenotype (Table 1) (see Appendix S1 for further details). 148

3 Table 1. Levels of evidence supporting medical management implications for particular phenotypes Chromosomal microarray impacts clinical management Level of evidence Description 1 Practice guideline endorsed by a professional society 2 Peer-reviewed publication making medical management recommendations 3 No peer-reviewed publications regarding management, but potential management implications based on clinical judgment 4 Could be managed symptomatically, regardless of underlying diagnosis Comparison to the ISCA database The ISCA Consortium is a group of laboratories, clinicians, and researchers dedicated to raising the standard of patient care by improving the quality of CMA testing ( One of the major efforts of the ISCA Consortium has been the establishment of a publically available database of de-identified CMA results from clinical testing laboratories around the world. Data from this database ( was accessed in March 2012 in order to evaluate the number of reported cases that overlapped with our previously defined clinically actionable regions of the genome. Genomic coordinates for the regions evaluated were obtained from each gene s entry in Gene ( (GRCh37/hg19). For phenotypes caused by loss-of-function mutations/haploinsufficiency, coordinates of the associated genes or regions were compared with all deletions within the ISCA Consortium database. For phenotypes caused by triplosensitivity, coordinates of the associated genes or regions were compared with all duplications within the ISCA Consortium database (see Appendix S1 for further details). Results Survey One hundred-eighty clinicians completed the survey, 85% from NSGC and 15% from ACMG. Most clinicians practiced predominantly in urban (n = 131; 72.7%) and pediatric (n = 119; 66.1%) settings. Although many respondents reported that CMA testing was warranted frequently among their patient populations (n = 88; 48.8%), only 18% of respondents reported actually ordering CMA testing every time it was indicated (n = 33). When queried regarding why CMA was not being ordered each time, respondents cited a lack of insurance coverage as the most frequent reason (n = 115; 63.8%), followed distantly by cost of testing (n = 65, 36.1%). Despite the discrepancies in ordering practice, most clinicians (n = 131; 72.8%) report being involved in cases in which CMA results Fig. 2. Reasons cited for chromosomal microarray analysis denial by third party insurance companies by clinician self-report. directly impacted clinical management; of these 131 individuals, 35% reported that this occurs frequently (>25% of cases). One hundred thirty-three respondents report receiving a denial from an insurance company for CMA testing (73.8%); 22 individuals report never receiving a denial (12.2%), while 25 did not answer the question (13.8%); 131 individuals responded to a multiple-answer question regarding reasons for these denials. Common reasons reported for insurance denial included: testing was considered experimental by the insurance company (73.3%); individual s policy had a genetic testing exclusion (63.4%); testing was deemed not medically necessary by the insurance company (55.7%); and testing was not believed to impact clinical management (48.1%) (Fig. 2). Phenotypes with clinical management implications Of the 186 phenotypes deemed potentially diagnosable by CMA (Table S1), approximately 79% (146 phenotypes) had level 1 or level 2 evidence discussing specific clinical management recommendations; these disorders were considered to have an impact on clinical management. Another approximately 18% (34 phenotypes) had no peer-reviewed recommendations, but were thought to have some interventions which could be deemed prudent based of clinical judgment, and approximately 3% (n = 6) would be managed the same way regardless of the identification of a specific underlying diagnosis. Evidence in database A total of 1744 of the 2657 deletion cases (66%) submitted to the ISCA Consortium as pathogenic or likely pathogenic overlapped or fell within the coordinates corresponding to the individual genes or genomic regions associated with the 140 loss-of-function phenotypes with level 1 or level 2 evidence. A total of 164 of the 1468 duplication cases (11%) submitted to the ISCA Consortium as pathogenic or likely pathogenic overlapped or fell within the coordinates 149

4 Riggs et al. Fig. 3. Deletions and duplications submitted to the International Standards for Cytogenomic Arrays ISCA Consortium database as pathogenic or likely pathogenic that potentially impact medical management (as defined by level 1 or level 2 supporting evidence). of the seven triplosensitivity phenotypes associated with level 1 or 2 evidence (Fig. 3). Combining deletions and duplications, CMA diagnoses associated with clinical management recommendations based on level 1 or 2 evidence represent 46% of all reported pathogenic or likely pathogenic CNVs submitted to the ISCA database as of March 2012 (1908 out of 4125). Potentially clinically actionable CNVs were found in approximately 7% of all cases (n = 28,526) in the database at the time of evaluation. Illustrative examples of CMA impacting clinical management In addition to the quantitative data presented above regarding cases with actionable results on CMA, we present two qualitative examples of the impact of CMA results on clinical management. In each case, results from the CMA impacted the patient s clinical management, allowed discussion of prognosis, and provided an answer to families for the cause of their child s clinical findings. Case example 1 CMA testing was recommended after a neurology consultation for a 5-year old boy due to intractable epilepsy and developmental delays. Dysmorphic facial features were not appreciated. Brain magnetic resonance imaging revealed a neuronal migration defect with heterotopic matter along the occipital and temporal horns of both lateral ventricles, in addition to a focally thickened region of gray matter in the inferomedial aspect of the right temporal lobe. CMA testing detected a mosaic 7.5 Mb terminal deletion from 17pter to 17p13.1 [genomic coordinates chr17:11,807-7,541,055 based on NCBI human genome build 36.1 (hg18)]. FISH studies confirmed the deletion and showed that it was present in approximately 70% of metaphases and 66.5% of interphase nuclei from a phytohemagglutinin-stimulated culture and 70.5% of interphase nuclei from an unstimulated sample. The deletion includes the PAFAH1B1 (LIS1 ) gene and is therefore consistent with a diagnosis of LIS1 -associated lissencephaly/subcortical band heterotopia (OMIM #607432). This diagnosis has management recommendations (including surveillance for onset of seizures and decline in respiratory status) based on level 2 evidence (22), but can generally be managed clinically. However, this particular deletion extends approximately 4 Mb past the PAFAH1B1 gene and includes TP53. Heterozygous loss-of-function mutations in TP53 are associated with Li Fraumeni syndrome (OMIM #151623) and predispose to numerous neoplasias at young ages (23). Management guidelines for Li Fraumeni syndrome have been published by the National Comprehensive Cancer Network (24) that include surveillance and lifestyle factors (such as the avoidance of ionizing radiation when possible) which would not have been considered based upon his clinical presentation alone. Case example 2 A 13-year old girl was evaluated by a clinical geneticist for dysmorphic features and developmental delays, and CMA testing was performed. A 556 kb deletion at Xp22.3 [genomic coordinates chrx:20,168,082-20,723,743 based on NCBI human genome build 36.1 (hg18)] was detected and confirmed by metaphase FISH. The deleted interval contains a portion of the RPS6KA3 gene, which causes Coffin Lowry (OMIM #303600) syndrome. The laboratory was not provided with a detailed clinical description of this patient, but was informed by the ordering physician that her clinical features were consistent with this diagnosis. While this condition can be suspected based on clinical findings, particularly in males, it is a rare disease that may not be familiar to physicians other than a medical geneticist. Further, this could be particularly difficult to diagnose in a female given the broad spectrum of clinical severity, which can range from normal development to severe cognitive impairment. A confirmed diagnosis of Coffin Lowry syndrome presents with management recommendations based on level 2 evidence (25, 26), such as recurrent surveillance for cardiac, musculoskeletal, dental, hearing, and ophthalmologic abnormalities, as well as minimizing the occurrence of stimuli that may trigger stimulus-induced drop attacks (SIDAs), present in 20% of affected individuals. Medications can be considered for treatment of epilepsy and/or SIDAs, and some individuals require protective equipment, such as wheelchairs, to prevent injuries resulting from neurologic symptoms. For this patient, CMA testing resulted in a clear diagnosis that explained her current clinical features and also informed clinical management considerations that might not have otherwise been considered. 150

5 Chromosomal microarray impacts clinical management Discussion Our survey results show that clinicians consider CMA standard of care for children with developmental disabilities, but they do not always order CMA because of real and perceived barriers, potentially creating disparities in care. Lack of reimbursement was cited as a barrier to testing. Perceived reasons for coverage denial included: policy exclusion for genetic testing, test considered experimental or not medically necessary, and concerns that results would not impact clinical management. Regarding the last point, some payer policies state that CMA testing is experimental and investigational because of insufficient evidence of its effectiveness (e.g. We leveraged the collective knowledge of numerous clinical testing laboratories who submitted their interpretations of CMA results into the publicly available ISCA Consortium database to show that, in at least 7% of all cases, a diagnosis by CMA testing should lead to specific clinical management implications. Although a 7% yield appears modest, it should be compared with other approved diagnostic tests which purport to influence clinical management. BRCA1 /2 testing for hereditary breast and ovarian cancer (OMIM #604370, #612555) is covered by many payers, each indicating specific patient populations for whom it is most appropriate (24). Diagnostic yields for this test among some subpopulations are comparable with what we report: women with breast cancer under the age of 50 (4.7%); women with epithelial ovarian cancer at any age and negative family history (7.7%); males with breast cancer and negative family history (6.9%), etc. (27). Individuals in these subgroups meet the criteria set forth by certain insurance policies to have this testing covered, presumably due at least in part to the impact these test results have on clinical management. We acknowledge that many of the disorders identified by CMA are not as amenable to intervention as hereditary breast cancer, but fragile X syndrome is a valid comparison with the disorders tested by CMA. Diagnostic genetic testing for fragile X is accepted standard of care in the evaluation of individuals with developmental delays, intellectual disability, and/or autism, indications also appropriate for CMA testing (4, 5, 7, 28). Our collective experience is that fragile X testing is a uniformly covered service. Diagnostic yield varies with population (<1% for individuals with ASD (29, 30), and up to 3.5% among individuals with DD or ID (31 34)), but is lower than our projected 7% yield of clinically actionable results, and well below the overall reported diagnostic yield of CMA testing, estimated at 15 20% for similar patient populations (8). A fragile X syndrome diagnosis is actionable in ways similar to the way we have measured actionability in our study, and illustrates the point that other genetic tests are covered by third party payers without the same levels of evidence supporting diagnostic yield and clinical utility that are being required of CMA testing. This may be due in part to the fact that fragile X testing has been recommended for certain populations by numerous professional groups, such as the American Academy of Pediatrics and the American Academy of Neurology. Groups such as these outside of the genetics realm, despite acknowledging its superior diagnostic yield (35), have been slower to clearly endorse CMA as a recommended test. Our estimate of CMA providing a 7% yield of clinically actionable results is likely a conservative one. First, we only evaluated genes that are targeted on the current ISCA Consortium 180K array design; although not technically targeted, the array does have the ability to detect aberrations involving other genes because of genomic backbone coverage (21). Involvement of these other genes could also contribute to clinical management implications. Further, technological developments will probably result in the ability to add higher density coverage for lower cost, potentially increasing diagnostic yield for actionable conditions. Second, 49 phenotypes were excluded as they were not potentially diagnosable due to alternative mechanisms including gain of function. Although uncommon, some phenotypes associated with gain of function could be identified by CMA. For example, Noonan syndrome is caused by gain-of-function mutations in PTPN11 and other genes in the RAS/MAPK pathway, and at least one case of 12q24 duplication involving PTPN11 as an uncommon cause of Noonan syndrome has been reported (36). Third, we only considered those diagnoses associated with documented clinical management recommendations for our estimates. Over time, it is likely that additional clinical management recommendations will emerge. Indeed, a number of genomic syndromes evaluated for this study have only been described within the last several years (2). Finally, ongoing clinical CMA testing and centralization of results through databases such as that of the ISCA Consortium will facilitate continual quality improvement of our collective CNV knowledge base, and some CNVs now considered benign might later be found to have a role in human disease. Medical knowledge regarding pathogenic CNVs will continue to evolve. Many CNVs are just recently described, and some of the complications of those CNVs may not yet be apparent. Although much of the prognostic information regarding CNVs has been generated primarily from the pediatric population, a single CNV may cause multiple medical issues throughout the lifespan. As an example, the 17q12 deletion syndrome (OMIM #614527), a recurrent microdeletion syndrome, shows variable expressivity of features which have the potential to emerge over time. It is recommended that individuals with this condition be evaluated and monitored longitudinally for all features associated with the condition, not just their initial presenting features (37). For example, individuals with this microdeletion should be assessed for diabetes, and if affected, should be managed according to recommendations put forth for maturity-onset diabetes of the young, or MODY, the specific type of diabetes for which they are at risk (38). 151

6 Riggs et al. Possible limitations of our study include that survey data reflects a bias toward proponents of CMA testing who are more motivated to respond, and results are not verifiable with actual payer data. However, even if the true number of medical providers foregoing CMA testing is smaller, it is still likely that some patients are indeed being affected by barriers to reimbursement. Another possible criticism is that we are not able to address patient outcomes after medical intervention/surveillance that was initiated by CMA testing. Although highly desirable, this information is not available in our database; our database is compiled from data from genetic testing laboratories which often do not have access to this type of information, and have little recourse to obtain it because of insufficient patient contact information, Health Insurance Portability and Accountability Act (HIPAA) privacy concerns, and limited resources. In order to study outcomes, we would need a large prospective cohort to be tested and followed for many years, perhaps decades, which is not practical and unlikely to be funded because of the rarity and diversity of conditions represented on CMA. We propose that, in lieu of this essentially unachievable ideal study, the findings herein be considered an approximation of the true impact on patient clinical management as a direct result of CMA testing. Supporting Information The following Supporting information is available for this article: Table S1. Phenotypes considered potentially diagnosable by cytogenomc Appendix S1. Determination of Clinical Actionability Additional Supporting information may be found in the online version of this article. Acknowledgements The authors would like to thank Erin Baldwin Kaminsky, Christa Lese Martin, and David H. Ledbetter for critical review of the manuscript. This work was supported by NIH Grant HD References 1. Manning M, Hudgins L. 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