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Shaikh, T. H., Gai, X., Perin, J. C., Glessner, J. T., Xie, H., Murphy, K. et al. High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res. 19, 1682-1690

Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Genome Research (Impact Factor: 13.85). 08/2009; 19(9):1682-90. DOI: 10.1101/gr.083501.108
Source: PubMed

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 African-Americans (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.

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    • "She also described some difficulties with fine motor skills and visual integration . Duplications of this region of chromosome 2q13 are not reported in normal CNV databases [Itsara et al., 2009; Shaikh et al., 2009; Macdonald et al., 2014] "
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    ABSTRACT: Copy number variation (CNV) in the long arm of chromosome 2 has been implicated in developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), congenital anomalies, and psychiatric disorders. Here we describe 14 new subjects with recurrent deletions and duplications of chromosome 2q11.2, 2q13, and 2q11.2-2q13. Though diverse phenotypes are associated with these CNVs, some common features have emerged. Subjects with 2q11.2 deletions often exhibit DD, speech delay, and attention deficit hyperactivity disorder (ADHD), whereas those with 2q11.2 duplications have DD, gastroesophageal reflux, and short stature. Congenital heart defects (CHDs), hypotonia, dysmorphic features, and abnormal head size are common in those with 2q13 deletions. In the 2q13 duplication cohort, we report dysmorphic features, DD, and abnormal head size. Two individuals with large duplications spanning 2q11.2-2q13 have dysmorphic features, hypotonia, and DD. This compilation of clinical features associated with 2q CNVs provides information that will be useful for healthcare providers and for families of affected children. However, the reduced penetrance and variable expressivity associated with these recurrent CNVs makes genetic counseling and prediction of outcomes challenging. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2015; DOI:10.1002/ajmg.a.37269 · 2.05 Impact Factor
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    • "tcag.ca/) including those by Itsara et al. (1/1557), Shaikh et al. (1/2026) and Xu et al. (3/6533) [Itsara et al., 2009; Shaikh et al., 2009; Xu et al., 2011]. This suggests that this change is likely to be benign. "
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    ABSTRACT: HEY2 is a basic helix-loop-helix (bHLH) transcription factor that plays an important role in the developing mammalian heart and brain. In humans, nonsynonymous mutations in HEY2 have been described in patients with atrial ventricular septal defects, and a subset of individuals with chromosomal deletions involving HEY2 have cardiac defects and cognitive impairment. Less is known about the potential effects of HEY2 overexpression. Here, we describe a female child with tetralogy of Fallot who developed severe right ventricular outflow tract obstruction due to a combination of infundibular and valvular pulmonary stenosis. She was also noted to have hypotonia, lower extremity weakness, fine motor delay and speech delay. A copy number variation (CNV) detection analysis followed by real-time quantitative PCR analysis revealed a single gene duplication of HEY2. This is the only duplication involving HEY2 identified in our database of over 70,000 individuals referred for CNV analysis. In the developing heart, overexpression of HEY2 is predicted to cause decreased expression of the cardiac transcription factor GATA4 which, in turn, has been shown to cause tetralogy of Fallot. In mice, misexpression of Hey2 in the developing brain leads to inhibition of neurogenesis and promotion of gliogenesis. Hence, duplication of HEY2 may be a contributing factor to both the congenital heart defects and the neurodevelopmental problems evident in our patient. These results suggest that individuals with HEY2 duplications should be screened for congenital heart defects and monitored closely for evidence of developmental delay and/or cognitive impairment. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2015; DOI:10.1002/ajmg.a.37086 · 2.05 Impact Factor
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    • "To reduce the possibility of type I error, only deletions spanning 5 consecutive SNPs and duplications spanning 10 consecutive SNPs were included. These CNV size thresholds were selected based upon previous studies from our group (Shaikh et al., 2009; Gai et al., 2010, 2012), examination of size-based concordance rates between the two algorithms (Fig. S1), and extensive experience with samples undergoing array-based clinical diagnostics at our institution (Conlin et al., 2010). In addition, all CNVs with SNP densities <1 SNP per 30 kb; CNVs with >50% overlap with centromere, telomere, and immunoglobulin variable regions; and olfactory receptor genes were removed before analysis (Hellemans et al., 2007; Hasin et al., 2008; Young et al., 2008; Elia et al., 2010; Gai et al., 2012). "
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    ABSTRACT: Background: We sought to characterize the landscape of structural variation associated with the subset of congenital cardiac defects characterized by left-sided obstruction. Methods: Cases with left-sided cardiac defects (LSCD) and pediatric controls were uniformly genotyped and assessed for copy number variant (CNV) calls. Significance testing was performed to ascertain differences in overall CNV incidence, and for CNV enrichment of specific genes and gene functions in LSCD cases relative to controls. Results: A total of 257 cases of European descent and 962 ethnically matched, disease-free pediatric controls were included. Although there was no difference in CNV rate between cases and controls, a significant enrichment in rare LSCD CNVs was detected overall (p = 7.30 × 10−3, case/control ratio = 1.26) and when restricted either to deletions (p = 7.58 × 10−3, case/control ratio = 1.20) or duplications (3.02 × 10−3, case/control ratio = 1.43). Neither gene-based, functional nor knowledge-based analyses identified genes, loci or pathways that were significantly enriched in cases as compared to controls when appropriate corrections for multiple tests were applied. However, several genes of interest were identified by virtue of their association with cardiac development, known human conditions, or reported disruption by CNVs in other patient cohorts. Conclusion: This study examines the largest cohort to date with LSCD for structural variation. These data suggest that CNVs play a role in disease risk and identify numerous genes disrupted by CNVs of potential disease relevance. These findings further highlight the genetic heterogeneity and complexity of these disorders. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 12/2014; 100(12). DOI:10.1002/bdra.23279 · 2.21 Impact Factor
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