Dataset Information

Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation.

ABSTRACT: The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically detectable chromosomal abnormalities are the most frequently recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy-number variants. We studied 100 children with idiopathic mental retardation and normal results of standard chromosomal analysis, by use of whole-genome sampling analysis with Affymetrix GeneChip Human Mapping 100K arrays. We found de novo deletions as small as 178 kb in eight cases, de novo duplications as small as 1.1 Mb in two cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy-number variants as conventional cytogenetic analysis can in people with mental retardation.

SUBMITTER: Friedman JM

PROVIDER: S-EPMC1559542 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation.

Friedman J M JM Baross Agnes A Delaney Allen D AD Ally Adrian A Arbour Laura L Armstrong Linlea L Asano Jennifer J Bailey Dione K DK Barber Sarah S Birch Patricia P Brown-John Mabel M Cao Manqiu M Chan Susanna S Charest David L DL Farnoud Noushin N Fernandes Nicole N Flibotte Stephane S Go Anne A Gibson William T WT Holt Robert A RA Jones Steven J M SJ Kennedy Giulia C GC Krzywinski Martin M Langlois Sylvie S Li Haiyan I HI McGillivray Barbara C BC Nayar Tarun T Pugh Trevor J TJ Rajcan-Separovic Evica E Schein Jacqueline E JE Schnerch Angelique A Siddiqui Asim A Van Allen Margot I MI Wilson Gary G Yong Siu-Li SL Zahir Farah F Eydoux Patrice P Marra Marco A MA

American journal of human genetics 20060725 3

The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically detectable chromosomal abnormalities are the most frequently recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy-number variants. We studie ...[more]

PMID: 16909388

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Project description:BACKGROUND: Microarray comparative genomic hybridization (CGH) is currently one of the most powerful techniques to measure DNA copy number in large genomes. In humans, microarray CGH is widely used to assess copy number variants in healthy individuals and copy number aberrations associated with various diseases, syndromes and disease susceptibility. In model organisms such as Caenorhabditis elegans (C. elegans) the technique has been applied to detect mutations, primarily deletions, in strains of interest. Although various constraints on oligonucleotide properties have been suggested to minimize non-specific hybridization and improve the data quality, there have been few experimental validations for CGH experiments. For genomic regions where strict design filters would limit the coverage it would also be useful to quantify the expected loss in data quality associated with relaxed design criteria. RESULTS: We have quantified the effects of filtering various oligonucleotide properties by measuring the resolving power for detecting deletions in the human and C. elegans genomes using NimbleGen microarrays. Approximately twice as many oligonucleotides are typically required to be affected by a deletion in human DNA samples in order to achieve the same statistical confidence as one would observe for a deletion in C. elegans. Surprisingly, the ability to detect deletions strongly depends on the oligonucleotide 15-mer count, which is defined as the sum of the genomic frequency of all the constituent 15-mers within the oligonucleotide. A similarity level above 80% to non-target sequences over the length of the probe produces significant cross-hybridization. We recommend the use of a fairly large melting temperature window of up to 10 degrees C, the elimination of repeat sequences, the elimination of homopolymers longer than 5 nucleotides, and a threshold of -1 kcal/mol on the oligonucleotide self-folding energy. We observed very little difference in data quality when varying the oligonucleotide length between 50 and 70, and even when using an isothermal design strategy. CONCLUSION: We have determined experimentally the effects of varying several key oligonucleotide microarray design criteria for detection of deletions in C. elegans and humans with NimbleGen's CGH technology. Our oligonucleotide design recommendations should be applicable for CGH analysis in most species.

Dataset Information

Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation.

Publications

Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation.

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