Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

Abstract

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.

Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

“…The overall detection rate in this series for clinically established pathogenic CNVs of 8.6% is comparable to other reported series/platforms [2,11,12,13,14,15,16,17,18,19,20], despite the inherent bias toward lower rates based on the real-world referral base and higher percentage of individuals with ASD in this population. When ASD is not among the testing indications, the rate of pathogenic findings is 12.5% and the overall diagnostic yield is 32.6%, both of which are at the upper end of reported diagnostic rates.…”

“…CMA yields significant rates of pathogenic or potentially pathogenic (VOUS) results [2,11,12,13,14,15,16,17,18,19,20], which have clinical utility for the case-by-case clinical management of individuals with these individually rare disorders [23,24,25,26,27,28,29,30,31,32,33,34]. …”

“…Collectively this trend has resulted in corresponding increases in the clinical value of CMA testing [11,12,13,14,15,16,17,18,19,20,21,24,25,26,27,28,29,30,31,32,33,34]. In addition to guidelines on the clinical indications for CMA, the American College of Medical Genetics and Genomics (ACMG) has issued guidance on the appropriate content and design of such arrays and specifically opined that, “It is desirable to have enrichment of probes targeting dosage-sensitive genes known to result in phenotypes consistent with common indications for a genomic screen (e.g., intellectual disability, developmental delays, autism, and congenital anomalies)” [22].…”

“…When ASD is not among the testing indications, the rate of pathogenic findings is 12.5% and the overall diagnostic yield is 32.6%, both of which are at the upper end of reported diagnostic rates. We have previously shown that diagnostic yield varies significantly on a multivariate basis including but not limited to: referring physician specialty, age of patient at testing, patient gender, and referring indication or combination of indications for testing [20]. When we look in this study at the influence of an ASD diagnosis on pathogenic diagnosis rates by practitioners, geneticists have the highest detection rate when there is no indication of ASD for testing, but also the lowest rate for individuals with ASD only.…”

“…Diagnostic yield has increased over time as such arrays have evolved to include better coverage [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21]. In 2011 the ACMG issued a guideline regarding optimal microarray design and recommended inclusion of additional probe content in areas of known clinical relevance [22].…”