Applying Chromosomal Microarray Analysis in Clinical Diagnosis
Dr. Vaidehi Jobanputra
Whole Genome Chromosome Microarray Testing
In the recent years, with the introduction of the whole genome chromosome microarray testing (CMA), diagnostic testing in pediatric and prenatal patients has undergone a marked evolution.
AGILE offers a whole genome, single nucleotide polymorphism [SNP] array for CMA testing. With this innovative technique, a patient’s genome is examined for detection of copy number variations (CNV) which are gains or losses of genetic material that typically are too small to be detectable by standard karyotype analysis or chromosome testing. This test is a whole genome scan and is much superior to subtelomere FISH (Fluoresence In Situ Hybridization) or microdeletion syndrome testing. In a single test, 100’s of microdeletion or micro-duplication syndromes are tested.
In addition to the CNVs, this test also detections “copy number neutral” abnormalities such as segmental uniparental disomy (UPD) and areas of long contiguous stretches of homozygosity that can give rise to disease, congenital anomalies, or cognitive impairment.
UPD is pertinent to imprinting disorders and recessive disorders caused by inheritance of a mutation within a long stretch of homozygosity.
CMA provides the most accurate diagnosis for patients, which in turn will, provide the clinician the opportunity to discuss treatment options, prognosis, and recurrence risks as well as to avoid unnecessary future testing.
Discussed below are the most common indications for CMA testing in pediatric and prenatal diagonsis.
CMA testing is recommended as a first-line test by the American College of Medical Genetics in the initial postnatal evaluation of children with following indications:
- Multiple anomalies not specific to a well-delineated genetic syndrome
- Apparently nonsyndromic Developmental Delay/Intellectual Disability
- Autism spectrum disorders
- Dysmorphic features
- Growth retardation, speech delay, and other less well-studied indications
The clinical sensitivity of this test in children with developmental delay, mental retardation, and/or congenital anomalies is at least 10~15% higher than that of conventional methods of chromosome testing – karyotyping and subtelomere FISH (Miller et al. 2010, Kearney et al. 2011).
Recent studies have shown the utility of CMA in prenatal diagnosis (Wapner et al. 2012), stillbirths(Reddy et al. 2012) and miscarriages. CMA testing is recommended for following conditions:
- Fetal abnormalities detected by ultrasound
- Abnormal maternal serum screening test result
- Advanced maternal age
- Family history of chromosome abnormality
- Spontaneous abortion
As in pediatric cases, the identification of an abnormal result may provide diagnosis, end the search for a cause, and help with risk assessment and the development of a plan of care at birth or plan for future reproduction.
Applying CMA for Clinical Diagnosis – Critical Factors
Case Selection: Several technology providers and sales representatives often make strong statements in favor of CMA. CMA is no doubt a very useful technique for detection of a wide range of microdeletion syndromes. It is also an effective replacement for FISH (Fluorescence In-Situ Hybridization) studies in several cases. Instead of adopting a ‘trial and error’ approach for ruling out suspected genetic conditions using FISH, we can directly scan the full genome for microdeletion and identify the exact causes. However, despite its several advantages, CMA does not replace the standard karyotype analysis for detecting balanced translocations. Hence, it is important to choose the right technique for each type of patient condition. A careful selection of cases and a combination of techniques (CMA and Karyotype) can provide a very clear diagnosis to the clinician
Choice of Chip: CMA technology has several applications in clinical diagnosis and research across multiple specialties. Accordingly there are wide varieties of chips available from various service providers. Choice of high resolution chips is critical for obtaining accurate results in a clinical setting and making correct diagnosis. With the low-resolution chip, accuracy and validity of the clinical diagnosis remains uncertain. Clinical decisions cannot be made on chips used in research setting.
Validation: Though there are several varieties of commercially available chips, not all the chips are validated for clinical diagnosis. Before adopting any configuration of chip, the chip should be validated for consistent performance in a clinical setting. Validation studies should include sensitivity, specificity and reproducibility of the test. In a clinical setting where the results of a test are used for diagnosis, prognosis, and patient management proper validation of the test becomes very important.
Interpretation: CMA being a whole genome scan provides extensive data on CNV variation including very small changes. Clinical decisions cannot be made based on just the information available from bioinformatics analysis. Identifying and interpreting the variation which have disease association and correlating the CNVs to the phenotype of the patient requires significant experience in a clinical setting.
Chromosomal Microarray technology holds immense promise for improved clinical diagnosis. This technique is now enabling the diagnosis of hitherto undiagnosed microdeletion syndromes which left the clinicians guessing about the exact cause of an observed phenotype. However, proper application of CMA in clinical diagnosis requires careful selection of cases, sample processing using a high resolution chip and a meaningful interpretation of the data.
Kearney H et al., (2011) Genet Med 13:680-685
Jobanputra V et al. (2005) Genet Med 7(2):111-8.
Miller D et al., (2010) Am J Hum Genet 86(5): 749-764.
Reddy U et al., (2012) N Engl J Med 367:2185-2193
Wapner R et al. (2012) N Engl J Med 367:2175-2184
About the Author
Dr. Vaidehi Jobanputra is the President and Founder of Advanced Genomics Institute and Laboratory Medicine. She also holds the position of Assistant Professor of Clinical Pathology and Cell Biology at the College of Physicians and Surgeons of Columbia University and is the Co-Director of the Clinical Cytogenetics Diagnostic Laboratory of New York Presbyterian Hospital and Laboratory of Personalized Genomic Medicine at Columbia University Medical Center. Dr. Jobanputra is certified in Clinical Cytogenetics and Molecular Genetics by American Board of Medical Genetics