Clinical and laboratory observation
Clinical Utility of Array Comparative Genomic Hybridization: Uncovering Tumor Susceptibility in Individuals with Developmental Delay

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Microarray-based comparative genomic hybridization can determine genome-wide copy number alterations at the kilobase level. We highlight the clinical utility of microarray-based comparative genomic hybridization in determining tumor susceptibility in 3 patients with dysmorphic features and developmental delay, likely decreasing both morbidity and mortality in these patients.

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Methods

Each patient was referred for a genetics evaluation to an academic medical center because of developmental delay, dysmorphic features, and/or congenital anomalies. A clinically available 44 000 probe oligonucleotide array (EmArray Cyto6000; Emory University, Atlanta, Georgia; or GenomeDx, GeneDx; Gaithersburg, Maryland) was used. This array has a detection rate of ∼500 kb with targeted coverage of telomeric, centromeric, and gene-rich regions at a resolution of ∼50 kb. Once an abnormality was

Discussion

Traditional techniques for detecting genomic copy number variations have been limited either to abnormalities that can be visualized under the microscope or to smaller deletions or duplications that could be detected by targeted florescence in situ hybridization (FISH) analysis. The drawback of FISH analysis is the requirement that the clinician already knows which area of the genome to target. In our cases, the deletion was not cytogenetically visible and could only have been detected by aCGH.

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    Occasionally, a CNV may be identified that, although unrelated to the patient’s reason for referral, may indicate presymptomatic status for a late-onset disorder or may reveal an ongoing clinically unrecognized condition (i.e., an incidental finding13). Some examples of these include deletions involving known tumor suppressor genes,14 male infertility due to deletions involving the AZF region on the Y chromosome,15 a deletion disrupting a gene for hereditary spastic paraplegia in a child referred for autism,16 etc. It is often not possible to specifically avoid interrogation of the types of loci mentioned in the aforementioned cases, because such findings may occur as part of a large CNV involving multiple genes.

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    In addition, the role of CNVs of particular genes with respect to cancer development is often unclear, and lists of individual genes associated with cancer predisposition are fluid, expanding, and often inaccurate.4 A case series by Adam et al1 described 3 pediatric patients with deletions of CPGs; 2 had TP53 deletions, and 1 had a STK11 deletion. None of the patients had developed cancer or were manifesting other signs of the syndromes associated with defects of these genes.

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    These include chromosome 17p13.3 duplication syndrome (MIM 613215),1 Miller-Dieker lissencephaly syndrome (MDLS [MIM 247200]),2 Charcot-Marie-Tooth disease type 1A (CMT1A [MIM 118220]),3 hereditary neuropathy with liability to pressure palsies (HNPP [MIM 162500]),4 Potocki-Lupski microduplication syndrome (PTLS [MIM 610883]),5 and Smith-Magenis microdeletion syndrome (SMS [MIM 182290]).6 The first clinical cases with 17p13.1 microdeletion syndrome (MIM 613776) were reported in 2009 and 20107–11 and were delineated further by Zeesman et al.,12 who described two individuals with similar clinical phenotypes carrying de novo deletions. This study helped narrow the critical genomic interval to <250 kb.

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    The clinical utility of microarray-based comparative genome hybridization has already proven useful in cases of cancer predisposition syndromes. Early detection of TP53, APC, PTEN, WT1, and RB1 deletions can significantly improve patient outcomes by optimizing medical management [22,23]. Although we have yet to find a safe and reliable way to normalize our patient’s total monoamine profile, our microarray data and subsequent literature review have allowed us make recommendations that will prolong the life of our patient by preventing cardiovascular disease.

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This work was not supported by any grant funds. The authors declare no conflicts of interest.

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