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: 5.47). 01/2009; 122(6):1310-8. DOI: 10.1542/peds.2008-0297
Source: PubMed


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, Oct 01, 2015
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    • "Microarray complete genome hybridization allows for high resolution, genome-wide screening for submicroscopic chromosomal imbalances. The technology has allowed screening of the entire genome for copy number variants and has proven useful in detecting imbalances in neonates with birth defects [2] and in patients with congenital heart disease [3,4]. A microarray analysis does not specifically assess if a gain in copy number alters or disrupts the expression of the genes, but partial gene duplications would be anticipated to disrupt gene function [5]. "
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    ABSTRACT: The pentalogy of Cantrell is rare clustering of congenital defects, first described by Cantrell and colleagues in 1958. The exact pathogenesis for the pentalogy remains unknown and no specific genetic abnormalities have been correlated; however, a failure of embryogenesis has been suspected. The microduplication of chromosome 15q21.3 (57,529,846 to 58,949,448) found in our patient with pentalogy of Cantrell has not been described previously. We describe a case of a newborn Caucasian male baby with prenatally diagnosed pentalogy of Cantrell and a novel maternally inherited copy number variant detected by chromosome microarray analysis. Among the genes within the duplicated region is ALDH1A2, encoding the enzyme retinaldehyde dehydrogenase type 2. Vital for retinoic acid synthesis during early development, ALDH1A2 has previously been demonstrated in animal models to have a strong association with congenital heart disease and diaphragmatic hernia, two key elements comprising pentalogy of Cantrell. It is possible that perturbation of retinoic acid levels during development secondary to this microduplication could underlie the pathology observed in the current case of pentalogy of Cantrell.
    Journal of Medical Case Reports 12/2013; 7(1):287. DOI:10.1186/1752-1947-7-287
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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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    ABSTRACT: Copy number alteration (CNA) is one type of genomic aberration that is often induced by genome instability and is associated with diseases such as cancer. Determination of the genome-wide CNA profile is an important step in identifying the underlying mutation mechanisms. Genomic data based on next-generation sequencing technology is particularly suitable for determination of high-quality CNA profile. Now is an important time to reevaluate the use of sequencing techniques for CNA analysis, especially with the rapid growth of the different targeted genome and whole-genome sequencing strategies. In this study, we provide a comparison of resequencing strategies, with regard to their utility, applied to the same hepatocellular carcinoma (HCC) sample for copy number determination. These strategies include whole-genome, exome, and restriction site-associated DNA (RAD) sequencing. The last of these strategies is a targeted sequencing technique that involves cutting the genome with a restriction enzyme and isolating the targeted sequences. Our data demonstrate that RAD sequencing is an efficient and comprehensive strategy that allows the cost-effective determination of CNAs. Further investigation of RAD sequencing data led to the finding that a precise measurement of the allele frequency would be a helpful complement to the read depth for CNA analysis for two reasons. First, knowledge of the allele frequency helps to resolve refined calculations of allele-specific copy numbers, which in turn identify the functionally important CNAs that are under natural selection on the parental alleles. Second, this knowledge enables deconvolution of CNA patterns in complex genomic regions. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Bioinformatics 08/2013; 29(22). DOI:10.1093/bioinformatics/btt481 · 4.98 Impact Factor
    • "Detection of deletions and translocations at DNA level depend upon the usage of gene micro-array technology. We suggest molecular cytogenetic studies using chromosomal microarray analysis (CMA) for those four cases with dysmorphic features of probable genetic origin.[18] "
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    ABSTRACT: The etiology of cleft lip (CL) and/or cleft palate (CP) has been extensively studied in industrialized countries and is suggested to be heterogeneous with increasing evidence that both genetic and environmental factors are operating. To evaluate this assertion in a developing country like Pakistan, a case finding cross-sectional study was completed from 1(st) July 2010 to 31(st) May 2011 for 100 cases of CL and/or CP referred to the Genetic Clinic of the Children's Hospital, Lahore, Pakistan. A clinical examination followed by necessary diagnostic work-up was completed for each case. The cause of CL and/or CP was clear in 18% of the children (n = 18). Environmental causes were found in 6 children (four mothers developed hyperthermia during the 2(nd) month of gestation, one mother was diabetic, and one mother was a known case of epilepsy and took sodium valproate throughout her pregnancy). Six children were suffering from known genetic malformation syndromes (each with Jarcho-Levin syndrome, Oral-Facial-Digital syndrome type XI, Oral-Duplication syndrome, Kabuki syndrome, Fronto-nasal dysplasia and Nager syndrome). Novel chromosomal aberrations were identified in 2 children. In 82% of the children (n = 82) the cause of oro-facial clefts remained unknown. Impact of gender and consanguinity on the development of CL and/or CP was also studied. Prevalence of CP was significantly more among female children as compared to that in males (P < 0.05). Associated anomalies were present in 18% of the cases, anomalies of the craniofacial region being the most common. These findings were compared with regional and international studies.
    Indian Journal of Human Genetics 04/2013; 19(2):136-43. DOI:10.4103/0971-6866.116103
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