Genomic Imbalances in Neonates With Birth Defects: High Detection Rates by Using Chromosomal Microarray Analysis

Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.
PEDIATRICS (Impact Factor: 5.3). 01/2009; 122(6):1310-8. DOI: 10.1542/peds.2008-0297
Source: PubMed

ABSTRACT Our aim was to determine the frequency of genomic imbalances in neonates with birth defects by using targeted array-based comparative genomic hybridization, also known as chromosomal microarray analysis.
Between March 2006 and September 2007, 638 neonates with various birth defects were referred for chromosomal microarray analysis. Three consecutive chromosomal microarray analysis versions were used: bacterial artificial chromosome-based versions V5 and V6 and bacterial artificial chromosome emulated oligonucleotide-based version V6 Oligo. Each version had targeted but increasingly extensive genomic coverage and interrogated>150 disease loci with enhanced coverage in genomic rearrangement-prone pericentromeric and subtelomeric regions.
Overall, 109 (17.1%) patients were identified with clinically significant abnormalities with detection rates of 13.7%, 16.6%, and 19.9% on V5, V6, and V6 Oligo, respectively. The majority of these abnormalities would not be defined by using karyotype analysis. The clinically significant detection rates by use of chromosomal microarray analysis for various clinical indications were 66.7% for "possible chromosomal abnormality"+/-"others" (other clinical indications), 33.3% for ambiguous genitalia+/-others, 27.1% for dysmorphic features+multiple congenital anomalies+/-others, 24.6% for dysmorphic features+/-others, 21.8% for congenital heart disease+/-others, 17.9% for multiple congenital anomalies+/-others, and 9.5% for the patients referred for others that were different from the groups defined. In all, 16 (2.5%) patients had chromosomal aneuploidies, and 81 (12.7%) patients had segmental aneusomies including common microdeletion or microduplication syndromes and other genomic disorders. Chromosomal mosaicism was found in 12 (1.9%) neonates.
Chromosomal microarray analysis is a valuable clinical diagnostic tool that allows precise and rapid identification of genomic imbalances and mosaic abnormalities as the cause of birth defects in neonates. Chromosomal microarray analysis allows for timely molecular diagnoses and detects many more clinically relevant genomic abnormalities than conventional cytogenetic studies, enabling more informed decision-making and management and appropriate assessment of recurrence risk.

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Available from: Sau Wai Cheung, Aug 18, 2015
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    • "Genome instability, including nucleotide mutations, chromosomal rearrangements and DNA dose aberrations, promotes genetic variation. Among these possible genomic aberrations, DNA copy numbers are of high diversity in normal human populations (Sharp et al., 2005) and are associated with various human diseases, such as birth defects (Lu et al., 2008) and neurodegenerative diseases (Walsh et al., 2008; Xu et al., 2008). "
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    • "An economic evaluation also demonstrated that in postnatal analysis, the preferential use of CMA instead of karyotype is cost effective (Regier et al. 2010). It is also relevant the high detection rate of genomic imbalances in neonates with birth defects shown by CMA (Lu et al. 2008). Although several studies have been published to date suggesting higher detection rates (Sahoo et al. 2006; Van den Veyver et al. 2009; Maya et al. 2010), prenatal CMA experience is still limited and no prospective studies have been addressed to demonstrate the clinical utility of this novel technology in prenatal settings. "
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    • "Locus-specific mutation rates for SNV are 2.0–2.5 × 10 −8 and have recently been shown to potentially differ in male versus female germ cells (Conrad et al., 2011); for CNV, new mutation rates can be substantially higher: between 10 −6 and 10 −4 , 100 to 10,000 times more frequent than in SNV (Lupski, 2007a). The latter figures implicate CNV in sporadic traits (Lupski, 2007a) including birth defects (Lu et al., 2008) and highlight the contribution of new mutation to individual mutational burden (Potocki et al., 1999). Either new or recent (i.e., arising in close relatives or " clan members " ) de novo mutations could substantially contribute to phenotypic extremes, such as birth defects and disease. "
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