Emerging Diagnostic Tool
Cytogenomic microarray analysis (CMA), which can involve comparative genomic hybridization (aCGH) and cytogenomic constitutional microarray analysis, has emerged as a novel diagnostic tool for individuals with unexplained developmental delay, autism spectrum disease, and mental retardation. aCGH is used in addition to clinical evaluation and conventional genetic testing.
For chromosomal microarray testing, highly specific oligonucleotide probes are designed and distributed throughout the genome, allowing for a whole genome survey in a single assay with very high resolution analysis. CMA, reports the Mayo Clinic, has quickly moved from research to the clinical setting and has emerged as the recommended first-tier postnatal test for individuals with multiple anomalies not specific to a well-delineated genetic syndrome, apparently nonsyndromic developmental delay/intellectual disability, and autism spectrum disorder.
Chromosomal microarray testing detects a genetic cause for these clinical features in 15–20% of cases, a substantial increase in the diagnostic yield in this patient population. For individuals with multiple miscarriages, infertility, or who are suspected of having sex chromosome abnormalities (such as Turner or Klinefelter syndromes), a conventional chromosome study remains the most appropriate test.
In a communique, “Clinical Utility of Chromosomal Microarray Testing,” the Mayo Clinic warns, however, that the interpretation of chromosomal microarray test results is a “complex and evolving process that is aided by collaboration between the clinician and clinical laboratory, particularly regarding the submission of detailed clinical information at the time of test referral. A genetic consultation is often of benefit to ensure the appropriate clinical interpretation of chromosomal microarray test results.”
And, it goes on to say, the rapid proliferation of array-based technology into clinical laboratories has led to a lack of uniform guidelines for the clinical interpretation of observed copy number variations, at times causing confusing results or conflicting reports between laboratories.
To address these issues, the International Standards for Cytogenomic Arrays (ISCA) Consortium, now consisting of about 160 international laboratories, including the Mayo Clinic, was formed with the goals of developing evidence-based standards for chromosomal microarray design, to build a public database of clinical array data as a resource for the clinical and research communities, and to utilize the database to develop standards and guidelines for the interpretation of copy number changes in the clinical setting.
The ISCA reports that its rapidly growing group of clinical cytogenetics and molecular genetics laboratories remains committed to improving the quality of patient care related to clinical using new molecular cytogenetic technologies, including aCGH and quantitative single nucleotide polymorphism analysis using microarrays or bead chip technology.
In an issue brief from the Leonard Davis Institute of Health Economics, Marian Reiff, Ph.D., et al., write, “New technologies have given us the ability to detect genomic variation at resolutions 50–100 times greater than earlier tests. The good news is that we can now detect variations that help explain developmental delays, autism, or multiple congenital anomalies in up to 20% of children.
“The bad news is that we can also detect small missing or extra pieces of chromosomes that remain unexplained: that is, we don’t know whether they have any clinical significance at all. The rapid pace of technological change may have outpaced the lab’s ability to interpret.”
Hopefully, organizations such as the ISCA consortium will continue to work with scientists and clinicians in facilitating interpretation of a whole new world of data and enable the clinical utility of advanced cytogenomic tools.