Identification of a rare de novo three-way complex t(5;20;8)(q31;p11.2;p21) with microdeletions on 5q31.2, 5q31.3, and 8p23.2 in a patient with hearing loss and global developmental delay: case report

<p>Abstract</p> <p>Background</p> <p>Complex chromosome rearrangements (CCRs), which involve more than two breakpoints on two or more chromosomes, are uncommon occurrences. Although most CCRs appear balanced at the level of the light microscope, many demonstrate cryptic, submicroscopic imbalances at the translocation breakpoints.</p> <p>Results</p> <p>We report a female with hearing loss and global developmental delay with a complex three-way unbalanced translocation (5;20;8)(q31;p11.2;p21) resulting in microdeletions on 5q31.2, 5q31.3, and 8p23.2 identified by karyotyping, microarray analysis and fluorescence in situ hybridization.</p> <p>Discussion</p> <p>The microdeletion of bands 8p23.2 may be associated with the hearing impairment. Furthermore, the characterization of this patient's chromosomal abnormalities demonstrates the importance of integrated technologies within contemporary cytogenetics laboratories.</p

Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications

Microdeletions and microduplications encompassing a ~593-kb region of 16p11.2 have been implicated as one of the most common genetic causes of susceptibility to autism/autism spectrum disorder (ASD). We report 45 microdeletions and 32 microduplications of 16p11.2, representing 0.78% of 9,773 individuals referred to our laboratory for microarray-based comparative genomic hybridization (aCGH) testing for neurodevelopmental and congenital anomalies. The microdeletion was de novo in 17 individuals and maternally inherited in five individuals for whom parental testing was available. Detailed histories of 18 individuals with 16p11.2 microdeletions were reviewed; all had developmental delays with below-average intelligence, and a majority had speech or language problems or delays and various behavioral problems. Of the 16 individuals old enough to be evaluated for autism, the speech/behavior profiles of seven did not suggest the need for ASD evaluation. Of the remaining nine individuals who had speech/behavior profiles that aroused clinical suspicion of ASD, five had formal evaluations, and three had PDD-NOS. Of the 19 microduplications with parental testing, five were de novo, nine were maternally inherited, and five were paternally inherited. A majority with the microduplication had delayed development and/or specific deficits in speech or language, though these features were not as consistent as seen with the microdeletions. This study, which is the largest cohort of individuals with 16p11.2 alterations reported to date, suggests that 16p11.2 microdeletions and microduplications are associated with a high frequency of cognitive, developmental, and speech delay and behavior abnormalities. Furthermore, although features associated with these alterations can be found in individuals with ASD, additional factors are likely required to lead to the development of ASD

Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication

<p>Abstract</p> <p>Background</p> <p>Interstitial deletions of 3q29 have been recently described as a microdeletion syndrome mediated by nonallelic homologous recombination between low-copy repeats resulting in an ~1.6 Mb common-sized deletion. Given the molecular mechanism causing the deletion, the reciprocal duplication is anticipated to occur with equal frequency, although only one family with this duplication has been reported.</p> <p>Results</p> <p>In this study we describe 14 individuals with microdeletions of 3q29, including one family with a mildly affected mother and two affected children, identified among 14,698 individuals with idiopathic mental retardation who were analyzed by array CGH. Eleven individuals had typical 1.6-Mb deletions. Three individuals had deletions that flank, span, or partially overlap the commonly deleted region. Although the clinical presentations of individuals with typical-sized deletions varied, several features were present in multiple individuals, including mental retardation and microcephaly. We also identified 19 individuals with duplications of 3q29, five of which appear to be the reciprocal duplication product of the 3q29 microdeletion and 14 of which flank, span, or partially overlap the common deletion region. The clinical features of individuals with microduplications of 3q29 also varied with few common features. <it>De novo </it>and inherited abnormalities were found in both the microdeletion and microduplication cohorts illustrating the need for parental samples to fully characterize these abnormalities.</p> <p>Conclusion</p> <p>Our report demonstrates that array CGH is especially suited to identify chromosome abnormalities with unclear or variable presentations.</p

Coarctation of the aorta and mild to moderate developmental delay in a child with a de novo deletion of chromosome 15(q21.1q22.2)

BACKGROUND: Deletion of 15q21q22 is a rare chromosomal anomaly. To date, there have been nine reports describing ten individuals with different segmental losses involving 15q21 and 15q22. Many of these individuals have common features of growth retardation, hypotonia and moderate to severe mental retardation. Congenital heart disease has been described in three individuals with interstitial deletion involving this region of chromosome 15. CASE PRESENTATION: We report a child with coarctation of the aorta, partial agenesis of corpus callosum and mild to moderate developmental delay, with a de novo deletion of 15q21.1q22.2, detected by the array Comparative Genomic Hybridization (CGH). We utilized chromosome 15-specific microarray-based CGH to define the chromosomal breakpoints in this patient. CONCLUSION: This is the first description of mapping of an interstitial deletion involving the chromosome 15q21q22 segment using the chromosome 15-specific array-CGH. The report also expands the spectrum of clinical phenotype associated with 15q21q22 deletion

Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis

Application of array-based comparative genomic hybridization to clinical diagnostics

Microarray-based comparative genomic hybridization (array CGH) is a revolutionary platform that was recently adopted in the clinical laboratory. This technology was first developed as a research tool for the investigation of genomic alterations in cancer. It allows for a high-resolution evaluation of DNA copy number alterations associated with chromosome abnormalities. Array CGH is based on the use of differentially labeled test and reference genomic DNA samples that are simultaneously hybridized to DNA targets arrayed on a glass slide or other solid platform. In this review, we examine the technology and its transformation from a research tool into a maturing diagnostic instrument. We also evaluate the various approaches that have shaped the current platforms that are used for clinical applications. Finally, we discuss the advantages and shortcomings of "whole-genome" arrays and compare their diagnostic use to "targeted" arrays. Depending on their design, microarrays provide distinct advantages over conventional cytogenetic analysis because they have the potential to detect the majority of microscopic and submicroscopic chromosomal abnormalities. This new platform is poised to revolutionize modern cytogenetic diagnostics and to provide clinicians with a powerful tool to use in their increasingly sophisticated diagnostic capabilities

A cytogeneticist's perspective on genomic microarrays

The identification of cytogenetic imbalance is an important component of clinical genetics. About 1 in 154 newborns has a chromosome abnormality. Conventional cytogenetic analysis has enabled the identification of microscopic alterations of the chromosomes. The development of fluorescence in situ hybridization (FISH) and other molecular methodologies has made possible the identification of submicroscopic aberrations. An additional development was comparative genomic hybridization (CGH), a method that directly compares two genomes for DNA copy differences. As first developed, the substrate for CGH analysis is normal metaphase chromosomes. Recently, CGH has been applied to microarrays (array CGH) constructed from large insert clones to identify chromosome imbalance. Array CGH has many advantages over conventional cytogenetic and molecular cytogenetic techniques. Array CGH can be comprehensive (genome-wide), high resolution, amenable to automation, rapid, and sensitive. We anticipate that array CGH will be employed in the clinical cytogenetics laboratory in the near future and will lead to the identification of the chromosomal basis of new syndromes and existing genetic conditions

Effects of ozone exposure during microarray posthybridization washes and scanning

The increasing prevalence of array-based comparative genomic hybridization in the clinical laboratory necessitates the implementation of quality control measures to attain accurate results with a high level of confidence. Environmental ozone is present in all industrialized cities and has been found to be detrimental to array data even at levels considered acceptable by US Environmental Protection Agency standards. In this study, we characterized the effect of ozone on microarray data on three different labeling platforms that use different fluorescent dyes (Cy3 and Cy5, Alexa Fluor 555 and Alexa Fluor 647, and Alexa Fluor 3 and Alexa Fluor 5) that are commonly used in array-based comparative genomic hybridization. We investigated the effects of ozone on microarray data by washing the array in variable ozone environments. In addition, we observed the effects of prolonged exposure to ozone on the microarray after washing in an ozone-free environment. Our results demonstrate the necessity of minimizing ozone exposure when washing and drying the microarray. We also found that washed microarrays produce the best results when immediately scanned; however, if a low-ozone environment is maintained, there will be little compromise in the data collected