By Zhenyuan Wang, Ph.D.
Laboratory Director, Athena Diagnostics, Inc.
Chromosomal Microarray (CMA) is the first tier diagnostic test recommended by the American College of Medical Genetics (ACMG),1,2 the American Academy of Neurology (AAN),3 the Child Neurology Society,3 the American Academy of Pediatrics,4 and the International Standard Cytogenomic Array (ISCA) Consortium5 for individuals who lack a sufficient specific history or features on physical examination to suggest a specific genetic (or non-genetic) cause for global developmental delay (GDD), intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorder (ASD). CMA permits the detection of copy number variations (CNVs) by the high resolution detection of chromosome segments involved in deletions, duplications, and long continuous stretches of homozygosity.
CMA is used to either confirm clinical diagnosis of syndromic neurodevelopmental disorders, or to establish a diagnosis for children who do not present with an obvious syndrome, who are too young for full expression of a suspected syndrome, or who may have an atypical presentation. Children less than age 6 years are considered to have global developmental delay (GDD) if they perform more than two standard deviations below age-matched peers in two or more aspects of development.6-8 CMA has the highest diagnostic yield of any single clinically available test for children with GDD, ID, MCA, and ASD.5 The yield for clinically significant copy number variations (CNVs) can be as high as 15% to 20%.2,10 CMA should also be considered when any indicated biochemical tests for metabolic disease and single gene analysis for disorder like Fragile X have been performed, and results are negative.
A meta-analysis of 21,698 patients with GDD, ID, MCA or ASD from 33 independent studies showed that CMA detected pathogenic genomic imbalances with an average diagnostic yield of 12.2%.5 The diagnostic yield is significantly higher than with karyotyping and targeted FISH analysis.5,11,13 This significant increase in diagnostic yield impacts patient care in several important ways. The identification of a pathogenic abnormality can lead to proper referrals to specialists, especially for known syndromes, and may lead to therapeutic interventions for certain specific learning disabilities and screening for known anomalies, such as cardiac defects. It can also minimize the number of diagnostic procedures that a patient is subjected to.
Health economic studies show that CMA is a cost-effective test compared to karyotyping as a first line genetic test in individuals with GDD.16,17 CMA leads to downstream cost savings that avoid the expense of laboratory tests looking for other possible causes for GDD, ID, MCA, and ASD. As a single test, the cost of CMA is generally higher than that of karyotyping. However, when taking into account the additional tests required in the karyotype- first route and the increased diagnostic yield of the CMA approach, CMA decreases total costs by an estimated 10% to 20%.16,17
Next generation sequencing (NGS) is being evaluated for the simultaneous analysis of a large number of genes to identify single gene causes of syndromes that have autism as a significant clinical feature in individuals with normal CMA testing. Recent improvement in NGS bioinformatics has allowed detection of gene deletion and duplication (i.e. CNVs) and may replace CMA in the future.
Medical Director Comment
CMA is recommended as the first tier diagnostic test in the evaluation of all children with global developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorders.
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