High-resolution mapping and analysis of copy number variations in the human genome: A data resource for clinical and research applications

Abstract

We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of Caucasians (65.2%) and AfricanAmericans (34.2%), was analyzed for CNVs in a single study using a uniform array platform and computational process. We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These nonunique CNVs mapped to 3272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications, and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics.

Questionable pathogenicity of FOXG1 duplication

“…8 This duplication is similar in size to the B3 Mb minimal duplicated region that includes FOXG1, c14orf32 and PRKD1 described in affected patients reported by Brunetti-Pierri et al 1 Patients carrying these small-sized duplications (cases 1 and 5 in Figure 1) were assessed as non-dysmorphic, so it is possible the healthy CHOP patient is yet to present with developmental problems, infantile spasms or other seizures. Alternatively, this case provides further evidence that FOXG1 duplication may be benign or incompletely penetrant.…”

“…In support of this notion, two other FOX genes, FOXF1 and FOXL2, encoding for the evolutionarily conserved family of transcription factors with a central role in development have been shown recently to be upregulated by non-coding copy-number variants mapping over 250 kb 5¢ from these genes. [7][8] Of note, FOXG1 expression is restricted to the brain, and thus more likely to be finely regulated by such distant enhancer(s) in a tissue-specific manner.…”

Copy number variation in patients with cervical artery dissection

“…We filtered our findings against CNVs detected by high-density platforms (4500 000 SNPs) in Caucasian individuals. [15][16][17] Many patients' CNVs that were absent from all analyzed controls showed some overlap with rare CNVs listed in the database of genomic variants (DGV). However, the value of DGV for CNV interpretation is limited, as DGV contains non-validated CNVs and many CNVs with overestimated lengths.…”

“…In the second step, we compared the rare CNVs detected in our patient samples with published CNVs in 2402 Caucasian healthy subjects (HapMap project, n ¼ 90; CHOP database, n ¼ 1327; and a recent CNV population study, n ¼ 985). [15][16][17] Rare CNVs that were detected among CeAD-patients but were absent from own control subjects, and from the aforementioned data sets were considered as CeAD-associated.…”

“…Thirtyfour of these CNVs were absent in 2402 Caucasian controls 16,17 and were considered as CeAD-associated. Eighteen of the CeADassociated CNVs contained coding sequences (Table 1).…”