Chromosomal microarray impacts clinical management

Abstract

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.

Clinical performance of the CytoScan Dx Assay in diagnosing developmental delay/intellectual disability

“…Using Human Genome Build 19 (Genome Reference Consortium GRCh37), CytoScan Dx Assay CNV coordinates were compared with the coordinates of actionable microarray findings listed in the study by Riggs et al 8 There were two matching classifications. In the first, if the Riggs region was characterized as a chromosomal region and did not have a specific gene implicated, then the region had to be fully enclosed within a CytoScan Dx Assay CNV region.…”

“…This difference in percentage could be due to the fact that their cohort was not a consecutive series but, rather, a freeze of a database to which many laboratories submit array results. Level 1 evidence is described as practice guidelines endorsed by a professional society, level 2 evidence is peer-reviewed publications available for making medical management recommendations, and level 3 evidence indicates that there are no relevant peer-reviewed publications but potential management implications may be warranted based on clinical judgment (see Riggs et al 8 for a full description of the evidentiary levels). The current study did not have a category for "likely pathogenic" as the Riggs cohort did, and the cytogeneticist interpreting the results of this study did so in isolation, i.e., did not have access to any clinical information about these patients and very little data regarding parental results.…”

“…It has also been reported that microarray analysis in support of a patient's standard of care impacts patient management up to 70% of the time. [7][8][9][10] Because clinical management decisions are sometimes subjective, the percentages vary. In two large retrospective studies representing slightly less than a total of 75,000 patients, it was estimated that 35-46% of patients with pathogenic cytogenetic findings and 7% of all patients would have some sort of change in clinical management based on microarray results.…”

“…In two large retrospective studies representing slightly less than a total of 75,000 patients, it was estimated that 35-46% of patients with pathogenic cytogenetic findings and 7% of all patients would have some sort of change in clinical management based on microarray results. 7,8 Two other studies reported on retrospective cohorts for which actual rates of clinical implications were available and found that more than 50% of all patients with abnormalities had clinical management changes based on microarray results. 9,11 Although microarrays are now common first-tier tests in this patient population and Original research article supported by medical guidelines from the American College of Medical Genetics and Genomics (ACMG), 12 the International Collaboration for Clinical Genomics (ISCA/ICCG), 5 and the American Academy of Neurology, 13 payer reimbursement for testing is inconsistent, indicating the need for additional systematic studies assessing the changes in patient management that occur as a result of microarray testing.…”

“…To determine how this relates to management implications, we assessed the clinical utility of the CytoScan Dx Assay by applying the Riggs criteria of actionability to the chromosomal abnormalities identified by the CytoScan Dx Assay. In 2013, Riggs et al 8 published an article describing 186 phenotypes that were clinically actionable, potentially diagnosable via CMA, and that are causally linked to specific genes and/or chromosomal loci (see Supplementary Table S1 online). They further ranked each phenotype according to the level of evidence available.…”