Chromosomal Microarray, Prenatal, Amniotic Fluid/Chorionic Villus Sampling
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Chromosomal abnormalities cause a wide range of disorders associated with birth defects and intellectual disability. Many of these disorders can be diagnosed prenatally by analysis of chorionic villi or amniocytes.
The most common reasons for performing cytogenetic studies for prenatal diagnosis include advanced maternal age, abnormal prenatal screen, a previous child with a chromosome abnormality, abnormal fetal ultrasound, or a family history of a chromosome abnormality. Chromosomal microarray (CMA) is a high-resolution method for detecting copy number changes (gains or losses) across the entire genome in a single assay and is sometimes called a molecular karyotype. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend the chromosomal microarray as a replacement for the fetal karyotype in patients with a pregnancy demonstrating 1 or more major structural abnormalities on ultrasound when undergoing invasive prenatal diagnosis.(1)
This CMA test utilizes >1.9 million copy number probes and approximately 750,000 single nucleotide polymorphism (SNP) probes for the detection of copy number changes and regions with absence of heterozygosity (AOH). Identification of regions of excessive homozygosity on a single chromosome could suggest uniparental disomy (UPD), which may warrant further clinical investigation when observed on chromosomes with known imprinting disorders. In addition, the detection of excessive homozygosity on multiple chromosomes may suggest consanguinity.
Prenatal diagnosis of copy number changes (gains or losses) across the entire genome
Determining the size, precise breakpoints, gene content, and any unappreciated complexity of abnormalities detected by other methods such as conventional chromosome and FISH studies
Determining if apparently balanced abnormalities identified by previous conventional chromosome studies have cryptic imbalances, since a proportion of such rearrangements that appear balanced at the resolution of a chromosome study are actually unbalanced when analyzed by higher-resolution chromosomal microarray
Copy number variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
When interpreting results it is important to realize that copy number variation is found in all individuals, including patients with abnormal phenotypes and normal populations. Therefore, determining the clinical significance of a rare or novel copy number change can be challenging. Parental testing may be necessary to further assess the potential pathogenicity of a copy number change.
While most copy number changes observed by chromosomal microarray testing can readily be characterized as pathogenic or benign, there are limited data available to support definitive classification of a subset into either of these categories. In these situations, a number of considerations are taken into account to help interpret results including the size and gene content of the imbalance, whether the change is a deletion or duplication, the inheritance pattern, and the clinical and developmental history of a transmitting parent.
The continual discovery of novel copy number variation and published clinical reports means that the interpretation of any given copy number change may evolve with increased scientific understanding.
Copy number changes with unknown significance will be reported when at least 1 gene is involved in a deletion >1 megabases (Mb) or a duplication >2 Mb.
The detection of excessive homozygosity may suggest the need for additional clinical testing to confirm uniparental disomy or to test for mutations in genes associated with autosomal recessive disorders consistent with the patient's clinical presentation that are present in regions of homozygosity. Regions with absence of heterozygosity (AOH) with unknown significance will be reported when >10 Mb. Whole genome AOH will be reported when >10% of the genome.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test does not detect balanced chromosome rearrangements such as Robertsonian or other reciprocal translocations, inversions, or balanced insertions. These abnormalities may be identified by chromosome analysis (see AF / Chromosome Analysis, Amniotic Fluid or CVS / Chromosome Analysis, Chorionic Villus Sampling)
This test does not detect all types and instances of uniparental disomy.
This test is not designed to detect low-level mosaicism, although it can be detected in some cases.
This test does not detect point mutations, small deletions or insertions below the resolution of this assay, or other types of mutations such as epigenetic changes.
The results of this test may be of uncertain clinical significance. In such cases, studies of additional family members may be required to help interpret the results.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Committee opinion no. 581: the use of chromosomal microarray analysis in prenatal diagnosis. American College of Obstetricians and Gynecologists Committee on Genetics. Obstet Gynecol 2013;122:1374-1377
2. Wapner RJ, Martin CL, Levy B, et al: Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012;367:2175-2184
3. Armengol L, Nevado J, Serra-Juhe C, et al: Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis. Hum Genet 2012;131:513-523
4. Breman A, Pursley AN, Hixson P, et al: Prenatal chromosomal microarray analysis in a diagnostic laboratory; experience with >1000 cases and review of the literature. Prenat Diagn 2012;32:351-361
5. South ST, Lee C, Lamb AN, et al: ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med 2013;15:903-909