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CMA, the First Tier Test for Global Developmental Delay, Autism, and Multiple Congenital Anomalies

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.

Dr. Joseph Higgins, Medical Director, Athena Diagnostics

Dr. Joseph Higgins, Medical Director, Athena Diagnostics

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.

 

 

 

 

References:

1. Kearney HM, South ST, Wolff DJ, et al. American College of Medical Genetics recommendations for the design and performance expectations for clinical genomic copy number microarrays intended for use in the postnatal setting for detection of constitutional abnormalities. Genetics in medicine : official journal of the American College of Medical Genetics 2011;13:676-9.

2. Manning M, Hudgins L, Professional P, Guidelines C. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genetics in medicine : official journal of the American College of Medical Genetics 2010;12:742-5.

3. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011;77:1629-35.

4. American Academy of Pediatrics. Genetic and Metabolic Testing on Children With Global Developmental Delay. Pediatrics 2012;129:e825.

5. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American journal of human genetics 2010;86:749-64.

6. Petersen MC, Kube DA, Palmer FB. Classification of developmental delays. Seminars in pediatric neurology 1998;5:2-14.

7. Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 2003;60:367-80.

8. Yeargin-Allsopp M, Murphy CC, Cordero JF, Decoufle P, Hollowell JG. Reported biomedical causes and associated medical conditions for mental retardation among 10-year-old children, metropolitan Atlanta, 1985 to 1987. Developmental medicine and child neurology 1997;39:142-9.

9. Association AP. Diagnostic and Statistical Manual of Mental Disorders (Fifth ed.). Arlington, VA: American Psychiatric Association; 2013.

10. Manning M, Hudgins L. Use of array-based technology in the practice of medical genetics. Genetics in medicine : official journal of the American College of Medical Genetics 2007;9:650-3.

11. Hochstenbach R, van Binsbergen E, Engelen J, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. European journal of medical genetics 2009;52:161-9.

12. Sagoo GS, Butterworth AS, Sanderson S, Shaw-Smith C, Higgins JP, Burton H. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genetics in medicine : official journal of the American College of Medical Genetics 2009;11:139-46.

13. Edelmann L, Hirschhorn K. Clinical utility of array CGH for the detection of chromosomal imbalances associated with mental retardation and multiple congenital anomalies. Annals of the New York Academy of Sciences 2009;1151:157-66.

14. Van Naarden Braun K, Autry A, Boyle C. A population-based study of the recurrence of developmental disabilities–Metropolitan Atlanta Developmental Disabilities Surveillance Program, 1991-94. Paediatric and perinatal epidemiology 2005;19:69-79.

15. Daniel A, Hook EB, Wulf G. Collaborative U.S.A. Data on Prenatal Diagnosis for Parental Carriers of Chromosome rearrangements: Risks of Unbalanced Progeny. In: Liss AR, ed. New York; 1988.

16. Trakadis Y, Shevell M. Microarray as a first genetic test in global developmental delay: a cost-effectiveness analysis. Developmental medicine and child neurology 2011;53:994-9.

17. Regier DA, Friedman JM, Makela N, Ryan M, Marra CA. Valuing the benefit of diagnostic testing for genetic causes of idiopathic developmental disability: willingness to pay from families of affected children. Clinical genetics 2009;75:514-21.

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