Array comparative genomic hybridization technology is now being used to provide a genome-wide screen for unexpected genomic imbalances. As a result, this technique has become a valuable clinical diagnostic test and is enabling rapid identification of microdeletions and microduplications in much larger numbers of patients, many of whom present with no obvious clinical diagnosis. One of the major impacts from this revolutionary technology is the ability to identify microduplications, thus enabling medical geneticists to correlate the findings with the clinical assessment, as with the patient described by Miller et al. However, discovery of microduplications also poses a challenge to clinicians owing to the lack of clinical description and wide phenotypic variability that appears to be characteristic of microduplications.
Oligo-based arrays have further improved the diagnostic capabilities of this test over the previous artificial-chromosome–based arrays derived from bacterial artificial chromosome/P1. The notable advantages of oligo-based arrays are: (a) better design flexibility, which allows avoidance of repetitive sequences and ability to select oligos with good performance; (b) increased robustness because of enhanced dynamic ranges (signal to background); and (c) higher reproducibility and greater precision in mapping of aberrations.
The genome contains many low-copy repeats that can lead to these rearrangements, primarily as a result of nonallelic homologous recombination. Chromosome 22q11.2 is such a region, it is gene rich and contains multiple region-specific low-copy repeats. These low-copy repeats are known to mediate genomic disorders in this region, including DiGeorge syndrome/velocardiofacial syndrome, cat-eye syndrome, der(22) syndrome, and the 22q11.2 microduplication syndrome. Although DiGeorge syndrome/velocardiofacial syndrome is the most frequently identified genomic disorder of the 22q11.2 region, with an estimated frequency of 1 in 4000 live births, only a small number of patients with microduplication of this region have been described to date, likely owing to the highly variable and mild phenotype that may escape syndromic identification. Although FISH analysis can potentially identify microduplication in the DiGeorge syndrome/velocardiofacial syndrome critical region, this analysis method requires accurate clinical assessment of the phenotype by the clinician, who must specifically request evaluation of interphase cells.
Our experience indicates that microduplications are also more likely than microdeletions to be inherited, making the identification of these copy- number changes even more important for accurate recurrence-risk counseling for these families. We are practicing in an exciting time, because many more new diseases will be described on the basis of copy-number variants identified through this important clinical test.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: S.W. Cheung, Department of Molecular and Human Genetics, Baylor College of Medicine.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: None declared.
Expert Testimony: None declared.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
- © 2009 The American Association for Clinical Chemistry