Miller et al. report a case of developmental delay with microduplication of 22q11.2. This case illustrates several important issues related to structural aberration in the genome and shows that resolution of cytogenomic analysis is important in clinical genomic disorders. In this patient diagnosis was made with only a moderately dense 244K array, whereas the older 2.6K bacterial artificial chromosome array failed to detect this 3-Mb duplication. New chips with much higher resolution are entering the market, such as the one million single nucleotide polymorphism genotyping chips and chips with probes targeted for tens of thousands of copy-number variations (CNVs). These high-density platforms enable detection of submicroscopic structural variants that could not previously be revealed. On the other hand, the ability to scan the genome at this high resolution also leads to new challenges. We now know that a vast number of such structural variations are present in the human genome, and it has been estimated that up to a thousand CNVs may be found between any 2 individuals(1). At the moment there is insufficient understanding about the biological role and clinical significance of gain or deletion in most of these CNVs. As in the patient described by Miller et al., it is not certain what phenotypic role is played by the de novo 8p22 duplication.
Although there is no good answer to the question of why genomic copy-number changes are common causes of developmental delay and mental retardation, CNVs have also been implicated in other neurodevelopment disorders, including autism and schizophrenia(2)(3). Duplication or gain of CNVs at 22q11.2 was found to be one of the recurrent structural changes among autistic patients. This structural change was inherited from the father in one case and sporadically with de novo duplication in another. A variable penetrance was observed in the family with inherited 22q11.2 gain, and the father who carried the same duplication was not affected. The latest research studies were carried out with a high-density single-nucleotide polymorphism–genotyping array, and the results suggested that CNV could be defined at an even higher resolution on these platforms. We are now facing a new dilemma. On one hand, it is tempting to apply the latest technology in clinical diagnostics. On the other hand, such an application will generate results that are so new that we do not have any understanding of their biological significance. Many more studies with large sample sizes and functional genetic experiments will be required to answer these questions.
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: No authors declared any potential conflicts of interest.
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