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Benign Copy Number Changes in Clinical Cytogenetic Diagnostics by Array CGH

ABSTRACT: A database of apparently benign copy number variants (bCNVs) detected by a Spectral Genomics Inc./PerkinElmer BAC array platform has been maintained through the University of Utah Comparative Genomic Hybridization laboratory since 2005. The target population for this database represents 1275 patients with abnormal phenotypes, primarily children referred for developmental delay and mental retardation. These bCNVs are independent of any identified copy number abnormality detected. The most common 35 bCNVs observed and their frequencies are reported here, and a subset of ten of the patients studied was evaluated on a new oligonucleotide CNV array set designed by Agilent Technologies. There was a 76% concordance of calls detected by both array platforms in the same patients; the discordant regions may be due to differences in reference DNAs, or false positive/negative results on either array. The higher resolution of the Agilent oligonucleotide array compared to the BAC array allowed for further characterization to determine precise breakpoints of the observed CNVs, in addition to documenting additional CNVs of smaller sizes. As expected, observed CNVs and their frequencies were generally consistent with those of other previously published and available databases, including the Database of Genomic Variants (http://projects.tcag.ca/variation/). The availability of these data should assist other clinical laboratories in the evaluation of CNVs of unknown clinical significance. The Cytogenetics Laboratory at the University of Utah has been using aCGH to evaluate DNA derived from blood of patients with developmental delay, mental retardation and “syndromic” or dysmorphic phenotypes since 2005. From this database, we were able to determine which clones represented sequences which were frequently deleted or duplicated in our patient population. We identified our most common CNV regions and then selected DNAs from ten patients who exhibited copy number changes of those common regions for further study with the Agilent CNV microarray set. Normal male or female DNA from Promega was used as a sex-mismatched control. In addition to the ten clinical specimens, two self-self experiments for two patient samples were analyzed to estimate a false positive rate and to fine tune the parameters used for data analysis. A replicate hybridization was performed on one patient to determine reproducibility.

ORGANISM(S): Homo sapiens

SUBMITTER: Peter Tsang

PROVIDER: E-GEOD-11815 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Benign copy number changes in clinical cytogenetic diagnostics by array CGH.

Whitby H H Tsalenko A A Aston E E Tsang P P Mitchell S S Bayrak-Toydemir P P Hopkins C C Peters G G Bailey D K DK Bruhn L L Brothman A R AR

Cytogenetic and genome research 20080101 1-4

A database of apparently benign copy number variants (bCNVs) detected by a Spectral Genomics Inc./PerkinElmer BAC array platform has been maintained through the University of Utah Comparative Genomic Hybridization laboratory since 2005. The target population for this database represents 1,275 patients with abnormal phenotypes, primarily children referred for developmental delay and mental retardation. These bCNVs are independent of any identified copy number abnormality detected. The most common ...[more]

PMID: 19287143

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Project description:Despite considerable excitement over the potential functional significance of copy number variants (CNVs), we still lack knowledge of the fine-scale architecture of the large majority of CNV regions in the human genome. In this study, we used a high-resolution array-based comparative genomic hybridization (aCGH) platform that targeted known CNV regions of the human genome at ~1 kb resolution to interrogate the genomic DNAs of 30 individuals from four HapMap populations. Our results revealed that 1,020 of 1,153 CNV loci (88%) were actually smaller in size than what is recorded in the Database of Genomic Variants based on previously published studies. A reduction in size of more than 50% was observed for 876 CNV regions (76%). We conclude that the total genomic content of common human CNVs may be smaller than previously thought. In addition, approximately 8% of the CNV regions observed in multiple individuals exhibited genomic architectural complexity in the form of smaller CNVs within larger ones and CNVs with inter-individual variation in breakpoints. Future association studies that aim to capture the potential influences of CNVs on disease phenotypes will need to consider how to best ascertain this previously underappreciated complexity. The DNA samples are a panel of 30 Hapmap samples, and a female sample NA15510 of undetermined geographic origin, which has been well characterized by fosmid-end sequencing (Tuzun et al. 2005, Nature Genetics 10, p1038). The DNA for this set of 16 female and 15 male samples are all supplied by the Coriell Cell Repository, and is comprised of samples from four populations: 10 unrelated Yoruban, 10 unrelated European-American individuals from Utah (CEPH), 5 unrelated Chinese, and 5 unrelated Japanese. The reference sample, NA10851 is also a male CEPH also from the HapMap Sample set (Corriel Cell Repository). Each of these samples was hybridized in pairs with the reversed labeling polarities. Additionally, 3 self-self control hybridizations were carried out for the reference sample, NA10851, one on each hybridization date. In the Title for each of the samples, each hybridization session is indicated by the letters A, B or C.

Dataset Information

Benign Copy Number Changes in Clinical Cytogenetic Diagnostics by Array CGH

Publications

Benign copy number changes in clinical cytogenetic diagnostics by array CGH.

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