Molecular Diagnosis of Autosomal Dominant Polycystic Kidney Disease
Jinghua Hu, Yong Yu in Polycystic Kidney Disease, 2019
Ultrasound examination of the kidney is the modality employed for initial screening. Understanding the progressive nature of ADPKD is important for diagnosis, leading to age-dependent imaging criteria. In the context of a positive family history of polycystic kidney disease, between age 18 and 39, the presence of at least three visible cysts is diagnostic of ADPKD.8 Due to the increasing prevalence of simple cysts with age, in a patient over age 60, four cysts must be visible in each kidney. Genetic testing can be useful to provide diagnostic certainty, often in the context of no apparent family history or equivocal imaging findings. A requirement for disease exclusion at a young age, such as in living donor transplant assessments or prenatal or preimplantation diagnostics, are additional indications for genetic testing. Scenarios for which genetic testing is being increasingly used in a clinical context include early and severe disease, risk stratification to identify “high-risk” patients for treatment with therapies associated with a therapeutic burden, marked intrafamilial discordance in disease severity, atypical imaging findings and discrepancy between imaging findings and decline in renal function, and suspicion of a phenocopy (i.e., autosomal dominant tubulointerstitial kidney disease) or syndromic (i.e., nephronophthisis) form of polycystic kidney disease.9,10
Genetic influences on antisocial behaviour, problem substance use and schizophrenia: evidence from quantitative genetic and molecular genetic studies
John C. Gunn, Pamela J. Taylor in Forensic Psychiatry, 2014
Parametric linkage analysis has been applied with considerable success in studies of Mendelian disorders, which have a single major disease locus with rare, highly penetrant alleles. Here, a number of genetic parameters for the disease under study can be specified, including a precise genetic model detailing the mode of inheritance, gene frequencies, penetrance rate ( frequency with which the disease phenotype manifests itself in the presence of the analysed gene) and phenocopy rate (the frequency with which the disease phenotype occurs in the absence of the analysed gene). Psychiatric disorders, however, do not have these straightforward characteristics of Mendelian disorders, and, as a result, it is much more difficult to define their genetic model. Parametric linkage analysis is therefore performed using large numbers of multiply affected pedigrees under several estimated genetic models. This remains a powerful gene mapping approach even in these circumstances, but the potential is considerable for both false positive results due to multiple testing and false negative results under the wrong genetic parameters. Successful linkage analysis in psychiatric disorders depends on overcoming the challenge posed by genetic and phenotypic heterogeneity.
Investigating the Role of Two-Pore Channel 2 (TPC2) in Zebrafish Neuromuscular Development
Bruno Gasnier, Michael X. Zhu in Ion and Molecule Transport in Lysosomes, 2020
Despite the fact that MOs have contributed greatly to the identification of hundreds of genes that are crucial for development, as well as to the elucidation of gene function, their use has recently been severely criticized due to their potential off-target effects (Eisen and Smith, 2008; Gerety and Wilkinson, 2011; Robu et al., 2007), as well as their failure to phenocopy the corresponding mutants (Kok et al., 2015). This led to the research community moving towards the use of permanent gene knock out techniques such as CRISPR/Cas9 gene-editing. However, reports now indicate that CRISPR/Cas9 might also be affected by off-targeting effects (Kuscu et al., 2014; Tsai and Joung, 2016). Indeed, it was recently suggested that the phenotypic discrepancies observed between some morphants and their corresponding mutants, might be due to the presence of genetic compensation in the mutants (Rossi et al., 2015). Thus, at least some of the differences observed between the morphants and the corresponding mutants might not just be attributable to the off-target effects of MOs; they might also be a result of the poor characterization of the mutants (Kok et al., 2015). However, with the appropriate controls, MOs can still be considered to be a reliable and valuable tool (Blum et al., 2015; Schulte-Merker and Stainier, 2014; Stainier et al., 2015, 2017). In addition, by using a combination of complementary transient-knock down (with MOs) and permanent-knock out (via CRISPR/Cas9), it is possible to obtain comprehensive data for a more thorough, comparable analysis.
N-acetyltransferase: the practical consequences of polymorphic activity in man
Published in Xenobiotica, 2020
It is important to differentiate between polymorphisms at the phenotype and genotype levels. They are not equivalent and must not be assumed to be so. Polymorphism at the phenotype level indicates differences in actual enzyme activity, a functional and measurable response in terms of substrate turnover that influences the proportion of an administered dose of drug moving through the body that undergoes a certain defined metabolic transformation. It provides a reflection of what is actually happening at that time and an overall “whole body” measurement of the examined process. This is what is of importance in the clinical situation. Polymorphisms at the genetic level indicate the possession of certain allelic variants that are known, via transcription and translation, to code for enzymes with certain characteristics. However, it is a long journey from gene to enzyme during which many variable and perhaps unknown epigenetic factors may intercede in an unclear manner, to influence, disrupt and obfuscate any attempt at direct transcendence. Association and interdependence of gene loci (e.g. multilocus haplotype frequencies, linkage disequilibrium and other phenomena) may also play a silent role. Genotype does not necessarily dictate phenotype. Hence, genotyping, although an excellent first approach, cannot replace phenotyping in the clinical situation. The emerging problems of “phenocopy” and “phenoconversion” must also be taken into account (Shah & Smith, 2012, 2015).
Immune checkpoint inhibition for the treatment of mesothelioma
Published in Expert Opinion on Biological Therapy, 2019
Anna K Nowak, Alison McDonnell, Alistair Cook
Finally, increasingly sophisticated bioinformatics provides many opportunities to enhance our understanding of immunotherapy in mesothelioma, and to consider rational combinations. For example, it is possible to interrogate RNA sequencing or RNA expression data for differences between responders and non-responders, both in animal models and in patient tumor datasets. Network analysis can identify gene hubs which could be further activated or suppressed to enhance the desired therapeutic response, and drug databases then interrogated for compounds which may phenocopy the optimal genetic profile of responders [88,89]. Most importantly, therapeutic combinations must not be solely driven by licensing or ownership of drug or antibody, but by a solid platform of preclinical evidence to support any clinical trial strategy. Only in this way will we successfully move new treatments to the clinic and study our limited pool of patients wisely.
Pharmacogenetics and drug metabolism: historical perspective and appraisal
Published in Xenobiotica, 2020
Robert L. Smith, Stephen C. Mitchell
The circumstances of individuals also may change from time to time, with various unappreciated factors taking their toll. The existence of certain disease states, comorbidities in a hospital situation, may lead to phenoconversion. Some HIV-positive subjects have been shown to display a CYP2D6 enzyme activity approaching that of a “poor metaboliser" phenotype although possessing an underlying “extensive metaboliser" genotype (O’Neil et al., 2000). Similar situations have arisen in patients with liver disease, undergoing liver transplantations and with certain cancers. The co-medication of prescription drugs, and the ingestion of over-the-counter preparations, may induce phenocopy, converting an “extensive metaboliser" genotype into a phenotypic “poor metaboliser". This latter phenomenon may last for a few hours to several days (Preskorn et al., 2013; Shah & Smith, 2012, 2015). Such confounding factors are not unsubstantial and must be taken into consideration.
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