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Clinical genetics
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
The total possible variation in the human genome is considerable. Studies have estimated that 12%–18% of the genome is subject to copy number variation. Over 38 million SNPs have been identified in different populations and each has been assigned a unique identifier. Any single individual will have between 3 and 4 million SNPs.
Biological individualisation of radiotherapy
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Catharine M.L. West, Robert G. Bristow, Adrian C. Begg
SNPs account for ∼90% of genetic variation in humans. Copy number variation (CNV) – deletions or duplications of large regions of DNA – is another type of genetic variation. High-density arrays can detect genome-wide CNV in tumours, and the percent of genomic alterations used as a surrogate of genomic instability (47) to develop a prognostic genomic classifier (46). In addition to genetic sequence variation, there can be epigenetic variation that includes methylation, acetylation, phosphorylation, ubiquitylation, sumoylation and chromatin modification. DNA methylation is the most widely studied. There is good evidence that MGMT methylation predicts benefit from the addition of temozolomide to radiotherapy in patients with brain tumours (34,51,67). This evidence led to trial testing alternative chemotherapeutics to give with radiotherapy in patients with non-methylated MGMT (35), highlighting how trials are moving towards biomarker-selected or biomarker-enriched populations.
Definition of an Allergen (Immunobiology)
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2014
Malcolm N. Blumenthal, Lauren Fine
Gene–gene interactions using multiple genes that interact in asthma and allergy may increase or even reduce the risk of disease development. Most gene–gene interaction studies appear to show an increase of asthma. Copy-number variation (CNV) is an alteration of the DNA of a genome that results in the cell having an abnormal number of copies on one or more sections of the DNA. They correspond to relatively large regions of the genome that have been deleted or duplicated on a certain chromosome. They may be either inherited or caused by de novo mutations. Most CNVs have little or no role in causing diseases such as asthma [43].
Determining the accuracy of next generation sequencing based copy number variation analysis in Hereditary Breast and Ovarian Cancer
Published in Expert Review of Molecular Diagnostics, 2022
Nihat Bugra Agaoglu, Busra Unal, Ozlem Akgun Dogan, Payam Zolfagharian, Pari Sharifli, Aylin Karakurt, Burak Can Senay, Tugba Kizilboga, Jale Yildiz, Gizem Dinler Doganay, Levent Doganay
Breast cancer (BC) and ovarian cancer (OC) are the leading causes of mortality and morbidity in women. BC and OC are mostly sporadic; however, up to 20% of all cases are hereditary [1,2]. Hereditary breast/ovarian cancer (HBOC) is mainly caused by the germline pathogenic variations of BRCA1 and BRCA2 genes. BRCA1/2 are tumor suppressors that play a role in DNA repair mechanisms for double-strand breaks via homologous recombination. Up to date, around 3000 pathogenic variations of BRCA1/2 are associated with HBOC [3]. Most of these are single nucleotide variants (SNVs) or small deletions/insertions, leading to a truncated protein. In addition, copy number variations (CNV) are also detected in around 10% of all the cases in different populations. The frequency of CNVs in BRCA1 and BRCA2 can be as high as 28% and 4%, respectively [4–9].
MicroRNA-copy number variations in coronary artery disease patients with or without type 2 diabetes mellitus
Published in Archives of Physiology and Biochemistry, 2021
Nasim Sohrabifar, Sayyed Mohammad Hossein Ghaderian, Hosein Vakili, Hamid Ghaedi, Borzu Rouhani, Hossein Jafari, Laleh Heidari
Copy number variations (CNVs) have been involved in the pathogenesis of common complex conditions, including coronary heart disease (CHD) (Costelloe et al.2012). So far, several studies implicated the association of CNVs of related susceptible genes with T2DM and CAD and the effect of these CNVs on the risk of disease (Wu et al.2014, Yan et al.2018). CNVs are prevalent in both coding and non-coding regions of the genome covering both genes and regulatory elements. MicroRNA (miRNA) genes composed about 4% of the coding genes across all chromosomes. miRNAs are small, 22 base RNA sequences that bind to a specific sequence in the 3´UTR of target coding genes and repress by the translation of these genes and, thereby, contribute in several significant biological processes (Hsu et al.2006). However, there are a few data about CNV of miRNA genes, and, to date, the presence of a few miRNAs in CNV regions and their potential consequences have been reported (Wong et al.2007, Lin et al.2008, Conrad et al.2010). The ability of miRNA for binding and regulation to target genes is influenced by CNVs in miRNA genes (Duan et al.2009).
Clinical genomics and contextualizing genome variation in the diagnostic laboratory
Published in Expert Review of Molecular Diagnostics, 2020
James R. Lupski, Pengfei Liu, Pawel Stankiewicz, Claudia M. B. Carvalho, Jennifer E. Posey
Copy-number variation can be benign or cause disease. The concept of gene/locus dosage as a surrogate biomarker for the disease trait peripheral neuropathy, was perhaps one of the first inventions (United States Patent and Trade Office, USPTO#s: 5,306,616; 5,780,223) to argue this concept. The locus variation resulting in gene dosage abnormalities, which can be due to an autosomal dominant (AD) trait segregating with the Charcot-Marie-Tooth disease type 1A locus duplication [8], could be a biomarker used to elucidate a molecular diagnosis responsible for neuropathy – even before the actual ‘causative gene’, PMP22, was established as the likely dosage-sensitive driver gene [9]. Of note, 20 years of clinical genetic testing, in >10,000 patients with clinical findings of peripheral neuropathy, has shown that ~80% of molecular diagnostic alleles are copy-number variants (CNV) at this PMP22 locus despite the observation that pathogenic variant alleles for dozens of genes, for this genetically heterogeneous disorder, can result in the CMT peripheral neuropathy trait [10].