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Recurrent Pregnancy Loss
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Reshama S. Navathe, Shabani Ahluwalia
Management of women with ≥2 RPLs should begin with genetic evaluation of products of conception (POCs) if possible (Figure 17.1) [15]. About 75% of early pregnancy losses in the first trimester result from random numeric chromosomal errors [16]. More than 50% of aneuploidies are trisomies; the most common single aneuploidy is 45,XO. Additionally, as maternal age increases, miscarriage associated with aneuploidy increases, accounting for up to 80% in those over 35 years of age [17]. Aneuploidy is typically considered sufficient explanation for pregnancy loss; this provides the couple with an explanation and has been shown to decrease self-blame [18]. Karyotype can be obtained directly from POCs; however, this test requires growing (dividing) cells to assess DNA in metaphase. Many times cells of abortuses do not grow in culture, especially those with aneuploidy. Potential pitfalls include culturing of maternal cell contaminants, falsely providing a “negative” test result (46,XX). Array comparative genomic hybridization (aCGH) does not require dividing cells and therefore can be useful in settings of culture failure. As such, aCGH has been suggested for use over karyotype.
Embryo Cell-Free DNA in the Culture Medium and Its Potential for Non-Invasive Aneuploidy Testing
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Carmen Rubio, Luis Navarro-Sánchez, Carmen M. García-Pascual
In 2016, Shamonki et al. established that the embryonic culture medium contained cfDNA and that this DNA could be used to detect embryonic aneuploidy [11]. DNA was found in most of the media samples after amplification (55 out of 57). While array comparative genomic hybridization (aCGH) could provide a diagnosis in only two of these samples, results in both cases were concordant with TE biopsy results from the same embryo. Subsequent studies also evaluated their SBM results via comparison with an established reference method, usually the TE biopsy. Comparisons are enabled by several validation measures, including: the ploidy concordance rate, or the overall agreement between the SMB and reference samples as euploid vs. aneuploid; the false positive rate, i.e., when the SBM is aneuploid and the reference sample is euploid; and the false negative rate, i.e., when the SBM is euploid and the reference sample aneuploid. An additional measure is the informativity rate of SBM, typically defined as the percentage of diagnosable SBM samples.
Comparative Genomic Hybridization and Copy Number Abnormalities in Breast Cancer
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
The progression of normal breast epithelial cells from a normal state toward one characterized by uncontrolled growth and metastatic behavior is caused by the deregulation of key cellular processes and signaling pathways. These alterations in normal cellular behavior are rooted in the accumulation of genomic and epigenomic lesions that impact hallmarks of cancer, such as the ability of the cell to control proliferation, undergo apoptosis, increase motility leading to invasion, and alter angiogenesis. A suite of technologies has now been developed to assess genomic and epigenomic aberrations that contribute to cancer progression. The application of these has shown that genome copy number abnormalities (CNAs) are among the most frequent genomic aberrations. Remarkably, these studies have revealed that 10% to 15% of the genes in a typical carcinoma tumor may be deregulated by recurrent genome CNAs and regions. Some of these genes influence disease progress and so may be assessed to facilitate prognosis. Others influence response to therapy and so may be assessed as predictive markers. Some of these enable oncogenic processes, on which tumors depend for survival, and so are candidate therapeutic targets. In most cases, array comparative genomic hybridization (CGH) is the method of choice for their discovery and may be used in some setting for clinical assessments of these abnormalities. Accordingly, we review here several of the current array CGH technologies available and the considerations needed when determining the technology most applicable to a given study.
Applying whole exome sequencing in a consanguineous population with autism spectrum disorder
Published in International Journal of Developmental Disabilities, 2023
Watfa Al-Mamari, Ahmed B. Idris, Khalid Al-Thihli, Reem Abdulrahim, Saquib Jalees, Muna Al-Jabri, Ahlam Gabr, Fathiya Al Murshedi, Adila Al Kindy, Intisar Al-Hadabi, Zandrè Bruwer, M. Mazharul Islam, Abeer Alsayegh
A total of 1346 confirmed cases of ASD were eligible to be included in the analysis. Among them, 749 underwent first-tier testing and 133 biochemical testing. Another 46 cases had further genetic testing. 321 cases were not tested for other reasons (parents declined testing, financial reasons or no appropriate sample was available for testing) (Figure 2). The remaining 97 children were included in the analysis, 63% were male and 37% were females (Table 1). The majority (84%) of the children were under the age of nine years, with an average age of 5.5 (SD 2.7) years. Most (89%) of the children included in the analysis had mothers within reproductive age (19–34 years), while 11% had mothers aged 35 years and older. The average age of the mothers at the time of birth was 27.6 years. The average age of fathers was 32.4 years. Array comparative genomic hybridization (array CGH) was done for three-quarters (75%) of the children, while more than half (55%) of the children had WES, performed as either solo (proband only sample analyzed) or trio (proband and parent’s sample analyzed). About one-third (34%) of the children had a positive diagnostic WES.
The first reported case of a deletion of the entire RPGR gene in a family with X-linked retinitis pigmentosa
Published in Ophthalmic Genetics, 2022
Nataša Mihailovic, Simone Schimpf-Linzenbold, Inga Sattler, Nicole Eter, Peter Heiduschka
Array comparative genomic hybridization was performed using the Agilent Sureprint G3 Unrestricted CGH ISCA 180k microarray providing complete coverage of the human genome and a practical resolution of 100kb for genomic losses and gains (copy number variants (CNVs)). Briefly, genomic DNA was isolated and amplified. The DNA was labelled with Cy3-dUTP, the reference DNA, sex matched human genomic DNA was labelled with Cy5-dUTP. The labelled test and reference DNA were combined and purified, and then loaded onto the chips and hybridized according to manufacturer’s instructions. Images of the array were acquired with Agilent surescan scanner and analyzed with Feature Extraction Software v5.0 (Agilent Technology, Santa Clara, CA, USA). The data was aligned to the reference genome described in NCBI Human Genome Build 19 and analyzed with CytoGenomics software v5.0 (Agilent Technology, Santa Clara, CA, USA). Databases used for the evaluation of detected variants include DECIPHER, DGV, ClinVar and gnomAD SV. Genes affected by the annotated CNVs were screened for clinical and functional relevance and listed in detail only if they might be clinically related to the patient’s phenotype at the time of analysis. The evaluation of variants is dependent on available clinical information at the time of analysis. Variants are named according to ISCN guidelines (2020).
Genetic variations as molecular diagnostic factors for idiopathic male infertility: current knowledge and future perspectives
Published in Expert Review of Molecular Diagnostics, 2021
Mohammad Karimian, Leila Parvaresh, Mohaddeseh Behjati
Microarray technology that evaluates males regarding copy number variation, gene expression level, and SNPs, is a promising approach for identification of very sensitive and specific biomarkers. Comparative genomic hybridization is a method that is applied for assessment of relative DAN ratios between samples and could be applied for whole-genome evaluation using microarray-based method or array comparative genomic hybridization. In the case of factors related to male infertility, array comparative genomic hybridization has identified Y-chromosomal microdeletion and other copy number variations outside of the identified AZF regions [189]. The additional candidate genes related to infertility are identified using array comparative genomic hybridization, although their roles are not yet clarified [190]. SNP analysis-based microarray has also recognized numerous candidate genes and potential biomarkers related to male infertility. This technique could also be a suitable alternative for reassessment of represented polymorphisms in this article with male infertility on wider scales.