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Molecular Diagnosis of Autosomal Dominant Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Matthew Lanktree, Amirreza Haghighi, Xueweng Song, York Pei
Regardless of the sequencing technology employed, putative variants in cystogenic genes will be identified that will require evaluation for pathogenicity. Quality control starts with examination of the electropherogram in capillary sequencing, or coverage, read depth, and sequencing quality scores in next generation sequencing technology. A BLAST search should be performed to determine if the variant sequence is found within pseudogene sequence, and thus likely due to a sequencing error. Next, identification of presence and frequency of the mutation in published control and case populations, cosegregation of the variant through family members when available, and bioinformatic prediction is required. Finally, creation of cell- or animal-based models can be considered.
Genetics of chronic pain: crucial concepts in genetics and research tools to understand the molecular biology of pain and analgesia
Published in Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen, Clinical Pain Management, 2008
Bradley E Aouizerat, Christine A Miaskowski
Initially, linkage studies can be used in a hypothesis-based evaluation of the cosegregation of gene variations in “candidate genes” with a trait.22 A candidate gene is defined as a gene that may contribute to a trait based on the biochemical properties of its gene product. Alternatively, one can identify genes in a hypothesis-free manner by screening a set of genetic markers that span the entire genome or discrete chromosomal segments. Linkage studies attempt to locate gene(s) that underlie the trait(s) of interest.5 Linkage approaches can be used in any organism for which pedigrees can be collected and in which a genetic marker set of sufficient density is available (e.g. human, mouse,23 dog,24 fruit fly,25,26 zebrafish27,28) to interrogate the genome.
Defining genetic changes associated with cutaneous malignant melanoma
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Mezbah U. Faruque, Jeffrey M. Trent
The purpose of linkage analysis is to evaluate the cosegregation of alleles at a particular locus with disease within families; that is, one examines the tendency for alleles, which are close to each other on the same chromosome to be transmitted together. Genetic linkage analysis requires identification and collection of individuals with histopathologically verified melanoma from melanoma-prone families and typing polymorphic markers at a chosen interval throughout the genome to identify the chromosomal locations of genes predisposing individuals to melanoma. The linkage of a putative disease locus and a marker locus is evaluated by measuring the number of recombination events between them with the recombination fraction (θ), which is the probability of an exchange of genetic material, i.e., cross-over between two loci. Linkage is often measured in terms of a LOD score, defined as the log10 of the ratio of two likelihoods: the (relative) probability of observing a given sibship at some particular recombination value relative to the probability of the family given no linkage.
Clinical and Genetic Analysis of Retinitis Pigmentosa with Primary Angle Closure Glaucoma in the Chinese Population
Published in Current Eye Research, 2022
Dan-Dan Wang, Feng-Juan Gao, Fang-Yuan Hu, Wen-Jun Cao, Ping Xu, Ying Huang, Xing-Huai Sun, Ji-Hong Wu
Peripheral blood was collected from all patients; genomic DNA was extracted from peripheral blood using the FlexiGene DNA Kit (Qiagen, Venlo, the Netherlands), in accordance with standard procedures. The capture panel in this study contained 586 genes and 30 bp on either side of the exonic region (Supplementary Table 1); the panel was established on the basis of information in the OMIM database, the ophthalmic disease gene database, and related literature. The panel was designed and produced by the Beijing Genomics Institute (BGI, Shenzhen, China). Enriched libraries were sequenced on the BGISEQ-500, with 100X minimum mean depth of coverage and 97.5% mean coverage of the target region. Reads were aligned to the hg38 human reference sequence using the Burrows-Wheeler aligner (version 0.7.10). The following five databases were used for the annotation: The Exome Aggregation Consortium (ExAC), the Genome Aggregation Database (gnomAD), dbSNP, 1000 Genomes Project, and 1000 Genomes in the East Asian population. Then, we retained variants with a minor allele frequency <0.1% to eliminate possible benign variants. Additionally, variant prioritizations were performed based on minor allele frequency, potential deleterious effect, and mutation reports in common databases such as OMIM, ClinVar, and the Human Gene Mutation Database. Finally, Sanger sequencing and cosegregation analyses were performed within families where available. Variants were classified in accordance with guidelines from the American College of Medical Genetics and Genomics guidelines.
Genotype-phenotype correlations of KIF5A stalk domain variants
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Eva M. J. de Boer, Wouter van Rheenen, H. Stephan Goedee, Erik-Jan Kamsteeg, Eva H. Brilstra, Jan H. Veldink, Leonard H. van Den Berg, Michael A. van Es
It can be challenging to determine the pathogenicity of rare variants found in single cases or families. A detailed family history to identify relatives with related phenotypes may be helpful. However, the feasibility of cosegregation analysis may be limited, especially in diseases with an adult onset, where older family members may already be deceased, and younger family members may carry the variant but not have symptoms (yet). This is of importance because false assignments of pathogenicity can have severe consequences for patients and their families (45). In this article we aimed to create a full overview of KIF5A variants, so all reported KIF5A variants are mentioned, however we did differentiate between variants that have an allele frequency over 1/1000, since this is used as cutoff in the clinical practice to counsel family members. It is also important to mention that the pathogenicity of the stalk mutations is not definite, as all the mutations reported are a VUS.
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
On the other hand, non-candidate gene approaches begin with a particular trait or phenotype and try to identify genes that are associated with it. Included in these approaches are genome-wide association studies (GWAS), genetic linkage analyses and so on. Genetic variants implicated by these studies are supported by robust statistical power and reproducibility. But most importantly, these studies enable the identification of previously unknown culprit genes [14]. A GWAS is a phenotype-first approach study where DNA of many individuals with and without a particular trait are analyzed and single-nucleotide polymorphisms (SNPs) that are associated with the trait are identified by statistical techniques [18]. Genetic linkage is phenomenon wherein genes physically located near each other on a chromosome are inherited together during meiosis. Linkage analyses are genetic association studies whereby culprit genes for a given condition are localized due to genetic linkage, i.e. due to their co-segregation with genes responsible for easily identifiable traits that tend to be inherited with the condition under consideration [19]. Like GWAS, these studies have been used to identify genes and DNA segments that were previously never implicated in the causation of a given condition. Beyond understanding the pathophysiology of arrhythmias, various genetic analyses have helped us unravel the molecular mechanisms of normal cardiac electrophysiologic function [14]. (Figure 1)