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Journal articles on the topic 'Genetic disorders; Disease genes'
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1
Coppedè, Fabio, Michelangelo Mancuso, Gabriele Siciliano, Lucia Migliore, and Luigi Murri. "Genes and the Environment in Neurodegeneration." Bioscience Reports 26, no. 5 (November 9, 2006): 341–67. http://dx.doi.org/10.1007/s10540-006-9028-6.
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Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene–environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and prion diseases.) and discuss possible links of gene–environment interplay including, where implicated, mitochondrial genes.
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RUTTER, MICHAEL. "Pathways of genetic influences on psychopathology." European Review 12, no. 1 (February 2004): 19–33. http://dx.doi.org/10.1017/s1062798704000031.
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Quantitative genetics, using data from twin and adoptee studies, has shown substantial genetic influences on all forms of psychiatric disorder; however, with just a few exceptions, the evidence indicates that the disorders are multifactorial, with influences that are both genetic and environmental. In recent years, molecular genetics has begun to identify individual susceptibility genes; examples are given for schizophrenia, attention deficit/hyperactivity disorder, and Alzheimer's disease. Both quantitative and molecular genetics have shown the importance of gene-environment interplay with respect to the commoner disorders of emotions and behaviour. In particular, it has been found that genetic influences moderate people's vulnerability to environmental risks. Five main alternative routes by which genes indirectly (via their effects on proteins) lead to multifactorial psychiatric disorders are described. Four main research issues are highlighted: the fuller delineation of the mechanisms involved in nature–nurture interplay and its role in aetiology; determination of how genes play a role in the neural underpinning of psychiatric disorders; identification of the ways in which genes suggest a dissection of disorders; and an understanding of the role of risk dimensions and disorder dimensions.
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Minaycheva, L. I., E. Yu Bragina, I. Zh Zhalsanova, N. A. Chesnokova, and A. V. Marusin. "Association of celiac disease genetic markers with reproduction disorders." Almanac of Clinical Medicine 47, no. 1 (February 26, 2019): 72–82. http://dx.doi.org/10.18786/2072-0505-2019-47-006.
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Background: Numerous studies have shown a link between genes involved in the immune response and infertility and miscarriage. The most significant associations have been established for the cytokine genes (IL1B, IL6, IL10, IL18), chemokine genes (CXCL9, CXCL10, CXCL11), and genes of the major histocompatibility complex HLA II class (DQA1, DQB1, DRB1). HLA genes are associated with celiac disease, a genetically determined autoimmune disorder, where male and female reproduction impairment is one of the symptoms. Aim: To assess the prevalence of polymorphic variants of the immune response genes (HLA: DQA1 DQB1, DRB1; TNF, IL10, CXCL10) in patients with reproduction disorders. Materials and methods: This pilot study involved assessment of the following gene polymorphisms: IL10 (rs1800872), TNF (rs1800629), CXCL10 (rs4386624), and HLA class II (DQA1, DQB1, DRB1) in couples (n = 220) with reproduction disorders (infertility and miscarriage). Genotyping was performed by real-time polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The genotypes and alleles population data were used for comparison with the studied variants of the genes IL10 (rs1800872), TNF (rs1800629), and CXCL10 (rs4386624). Differences in the prevalence of alleles and genotypes were assessed by χ2 test. The differences were considered significant at p < 0.05. Haplotype diversity was calculated by the Arlequin software, version 3.5.x. Results: Compared to the populational data, there was significant re-distribution of the genotypes and alleles to the TNF gene (rs1800629) variant in men with impaired reproductive functions. No differences were found for other gene variants studied. The frequency of HLA class II gene (DQA1, DQB1, DRB1) haplotypes associated with celiac disease (DQ2 and DQ8) in the study sample was 23.8%. Conclusion: The results indicate the important role of genes associated with celiac disease in the development of reproduction disorders.
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Cordeiro Júnior, Quirino, Daniela Meshulam Werebe, and Homero Vallada. "Darier's disease: a new paradigm for genetic studies in psychiatric disorders." Sao Paulo Medical Journal 118, no. 6 (November 9, 2000): 201–3. http://dx.doi.org/10.1590/s1516-31802000000600011.
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CONTEXT: One strategy for identifying susceptibility genes for common disorders is to investigate Mendelian diseases, cosegregating with these common disease phenotypes. CASE REPORT: A family with seven members is described, in which three members present Darier's disease and depression. This apparent cosegregation, if true, would support the hypothesis that in some pedigrees, a gene for mood disorder may be located on chromosome 12.
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Domschke, K. "Genetics in anxiety disorders - an update." European Psychiatry 26, S2 (March 2011): 2097. http://dx.doi.org/10.1016/s0924-9338(11)73800-7.
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Twin studies propose a strong genetic contribution to the pathogenesis of anxiety disorders with a heritability of about 50%. The dissection of the complex-genetic underpinnings of anxiety disorders requires a multi-level approach using molecular genetic, imaging genetic, (cognitive)-behavioral genetic and pharmacogenetic techniques linking basic and clinical research.The present talk will first give an overview of results from linkage and association studies yielding support for several candidate genes contributing to the genetic risk for anxiety and panic disorder in particular such as the adenosine 2A receptor, the catechol-O-methyltransferase, the neuropeptide S receptor and the serotonin receptor 1A genes. Results from the first genome-wide association studies in the field of anxiety disorders will be discussed. Additionally, studies on gene-environment interactions between anxiety disorder risk variants and environmental factors will be presented. Imaging genetics approaches have yielded evidence for several risk genes to crucially impact activation in brain regions critical for emotional processing. Gene variation has furthermore been found to potentially confer an increased risk for panic disorder via elevated autonomic arousal and dysfunctional cognitions regarding bodily sensations. Finally, there is first evidence for genetic variants impacting treatment response to antidepressant pharmacotherapy in anxiety disorders.Thus, converging lines of evidence will be presented for several candidate genes of anxiety to exert an increased disease risk potentially via a distorted cortico-limbic interaction during emotional processing, increased physiological arousal or dysfunctional cognition. Additionally, a possible impact of genetic variants on pharmacoresponse in anxiety disorders and its potential clinical implications will be discussed.
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Pajovic, Snezana. "Polygenic and miltufactorial disorders." Genetika 39, no. 2 (2007): 283–90. http://dx.doi.org/10.2298/gensr0702283p.
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Many factors influence our susceptibility to disease. These include our stress load, our environment and the toxins we absorb from it, the total number of infectious agents we are exposed to as well as our underlying genetic susceptibility to these diseases. Multifactorial is the term given to the mode of transmission shown by a large number of diseases which show familial clustering but which is not in accord with any recognized pattern of single gene inheritance. These diseases include several common congenital malformations and acquired disorders of childhood and adult life. The underlying genetic mechanism is thought to involve interaction of relatively large numbers of genes - hence oligogenic or polygenic - with environmental factors. The ultimate cause of Alzheimer?s (AD) is unknown. Genetic factors are suspected, and dominant mutations in three different genes have been identified that account for a much smaller number of cases of familial, early -onset AD. For the more form of late onset AD, ApoE is the only repeatedly confirmed susceptibility gene. Coronary artery disease is well-recognized complication of several single-gene disorders involving lipid metabolism. Over 20 genes have been proposed as candidates for polygenic coronary artery disease. These include genes which control lipid metabolism, blood pressure, clotting, and fibrinolysis.
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Ablon, Joan. "Social Dimensions of Genetic Disorders." Practicing Anthropology 14, no. 1 (January 1, 1992): 10–13. http://dx.doi.org/10.17730/praa.14.1.b800n7x364516715.
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Each of us carries between 4-8 recessive genes for serious genetic defects, and, hence, stands a statistical chance of passing on a serious or lethal condition to each child… 12 million Americans carry true genetic disease due wholly or partly to defective genes or chromosomes…40 percent or more of all infant mortality results from genetic factors…4.8 to 5 percent of all live births have genetic defects. (U.S. Department of Health, Education, and Welfare. "What are the Facts About Genetic Disease?" National Inst. of Gen. Med. Scs., P.H.S., N.I.H. DHEW Pub. No. (NIH), 75-370, 1975.)
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van Moorsel, Coline H. M., Joanne J. van der Vis, and Jan C. Grutters. "Genetic disorders of the surfactant system: focus on adult disease." European Respiratory Review 30, no. 159 (February 16, 2021): 200085. http://dx.doi.org/10.1183/16000617.0085-2020.
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Genes involved in the production of pulmonary surfactant are crucial for the development and maintenance of healthy lungs. Germline mutations in surfactant-related genes cause a spectrum of severe monogenic pulmonary diseases in patients of all ages. The majority of affected patients present at a very young age, however, a considerable portion of patients have adult-onset disease. Mutations in surfactant-related genes are present in up to 8% of adult patients with familial interstitial lung disease (ILD) and associate with the development of pulmonary fibrosis and lung cancer.High disease penetrance and variable expressivity underscore the potential value of genetic analysis for diagnostic purposes. However, scarce genotype–phenotype correlations and insufficient knowledge of mutation-specific pathogenic processes hamper the development of mutation-specific treatment options.This article describes the genetic origin of surfactant-related lung disease and presents spectra for gene, age, sex and pulmonary phenotype of adult carriers of germline mutations in surfactant-related genes.
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Ahmed, Hala, Louai Alarabi, Shaker El-Sappagh, Hassan Soliman, and Mohammed Elmogy. "Genetic variations analysis for complex brain disease diagnosis using machine learning techniques: opportunities and hurdles." PeerJ Computer Science 7 (September 20, 2021): e697. http://dx.doi.org/10.7717/peerj-cs.697.
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Background and Objectives This paper presents an in-depth review of the state-of-the-art genetic variations analysis to discover complex genes associated with the brain’s genetic disorders. We first introduce the genetic analysis of complex brain diseases, genetic variation, and DNA microarrays. Then, the review focuses on available machine learning methods used for complex brain disease classification. Therein, we discuss the various datasets, preprocessing, feature selection and extraction, and classification strategies. In particular, we concentrate on studying single nucleotide polymorphisms (SNP) that support the highest resolution for genomic fingerprinting for tracking disease genes. Subsequently, the study provides an overview of the applications for some specific diseases, including autism spectrum disorder, brain cancer, and Alzheimer’s disease (AD). The study argues that despite the significant recent developments in the analysis and treatment of genetic disorders, there are considerable challenges to elucidate causative mutations, especially from the viewpoint of implementing genetic analysis in clinical practice. The review finally provides a critical discussion on the applicability of genetic variations analysis for complex brain disease identification highlighting the future challenges. Methods We used a methodology for literature surveys to obtain data from academic databases. Criteria were defined for inclusion and exclusion. The selection of articles was followed by three stages. In addition, the principal methods for machine learning to classify the disease were presented in each stage in more detail. Results It was revealed that machine learning based on SNP was widely utilized to solve problems of genetic variation for complex diseases related to genes. Conclusions Despite significant developments in genetic diseases in the past two decades of the diagnosis and treatment, there is still a large percentage in which the causative mutation cannot be determined, and a final genetic diagnosis remains elusive. So, we need to detect the variations of the genes related to brain disorders in the early disease stages.
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Camp, G. Van. "Strategies for identification of disease genes." Acta Neuropsychiatrica 11, no. 2 (June 1999): 38–41. http://dx.doi.org/10.1017/s0924270800036103.
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Many genetic disorders are caused by mutations in single genes (monogenic diseases), and the inheritance pattern of these diseases follows simple rules. If a mutation in both copies of the gene on both chromosome homologues is necessary to cause the disease, the inheritance pattern is recessive, and a patient is the offspring of two clinically unaffected carriers. However, if a mutation in a single homologue is sufficient, the inheritance pattern is dominant and the disease is transmitted from generation to generation. Monogenic diseases are responsible for only a small fraction of all patients with genetic diseases. Many common diseases, including cancer, heart disease, diabetes and several psychiatric diseases, are the results of a complex interaction between genetic and environmental factors. However, these diseases can have important genetic components and can therefore still be considered genetic diseases. The identification of genes involved in complex genetic diseases can be very important for the understanding and treatment of these diseases. Over the last 15 years, much progress has been made in the identification of genes responsible for monogenic diseases, but the identification of genes involved in complex diseases has been more difficult, and at this moment little is known about the genes involved in most common diseases.
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Zampatti, Stefania, Michele Ragazzo, Cristina Peconi, Serena Luciano, Stefano Gambardella, Valerio Caputo, Claudia Strafella, Raffaella Cascella, Carlo Caltagirone, and Emiliano Giardina. "Genetic Counselling Improves the Molecular Characterisation of Dementing Disorders." Journal of Personalized Medicine 11, no. 6 (May 26, 2021): 474. http://dx.doi.org/10.3390/jpm11060474.
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Dementing disorders are a complex group of neurodegenerative diseases characterised by different, but often overlapping, pathological pathways. Genetics have been largely associated with the development or the risk to develop dementing diseases. Recent advances in molecular technologies permit analyzing of several genes in a small time, but the interpretation analysis is complicated by several factors: the clinical complexity of neurodegenerative disorders, the frequency of co-morbidities, and the high phenotypic heterogeneity of genetic diseases. Genetic counselling supports the diagnostic path, providing an accurate familial and phenotypic characterisation of patients. In this review, we summarise neurodegenerative dementing disorders and their genetic determinants. Genetic variants and associated phenotypes will be divided into high and low impact, in order to reflect the pathologic continuum between multifactorial and mendelian genetic factors. Moreover, we report a molecular characterisation of genes associated with neurodegenerative disorders with cognitive impairment. In particular, the high frequency of rare coding genetic variants in dementing genes strongly supports the role of geneticists in both, clinical phenotype characterisation and interpretation of genotypic data. The smart application of exome analysis to dementia patients, with a pre-analytical selection on familial, clinical, and instrumental features, improves the diagnostic yield of genetic test, reduces time for diagnosis, and allows a rapid and personalised management of disease.
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Grzywacz, Anna, Małgorzata Ryder, Iwona Małecka, and Jolanta Chmielowiec. "The current state of research on psychiatric genetics in Poland and the world: A report covering recent years." Postępy Higieny i Medycyny Doświadczalnej 72 (January 12, 2018): 1–12. http://dx.doi.org/10.5604/01.3001.0010.7979.
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The aim of this article was to review the results of research carried out in recent years in relation to genetic studies in psychiatry. The authors’ focus is on the selected disorders, with particular emphasis on the reports from Poland. For this purpose, the most often mentioned studies describing genes and biomarkers involved in psychiatry were selected. Genetic polymorphisms were described in relation to schizophrenia, alcoholism, addiction to psychoactive substances, autistic spectrum, unipolar depression and bipolar disorder, eating disorders and other psychiatric disorders. Characterizing the impact of inheritance factors on the processes in the central nervous system, it can be observed that some biological mechanisms forms associations with tested genetic variants and this combination is linked with the risk of mental disorders. To understand the role of psychiatric genetics, surveys which join genotype and phenotype associations (endophenotype) are essential. It seems important to study and search for associations of genes polymorphisms and biomarkers with mental and psychiatric disorders in order to better understanding the biological basis of the disease and more effective treatment of patients. In many cases, the variability analysis of selected genes sheds new light on understanding the etiology of diseases and mental disorders. Genetics is a powerful technique which allows us to study the impact of the inherited variance on changes in mental state, even without having prior knowledge about biological changes.
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Chung, Brian K., and Tom H. Karlsen. "Genetic Discoveries Highlight Environmental Factors as Key Drivers of Liver Disease." Digestive Diseases 35, no. 4 (2017): 323–33. http://dx.doi.org/10.1159/000456583.
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Background: Over the last 50 years, genetic studies have uncovered a spectrum of rare and common alleles that confer susceptibility to both Mendelian and complex forms of liver disease. For disorders of Mendelian inheritance, identification of the causal variants has demonstrated that common environmental exposures can elicit severe liver pathogenesis in predisposed individuals. Specific environmental triggers for complex liver disorders are largely unknown; however, large-scale association studies indicate that environmental triggers are the predominant factors in driving liver pathophysiology. Key Messages: In Mendelian liver disorders, a single rare variant of major effect is often responsible for disease development. Gene-sequencing technologies have greatly facilitated the discovery of causal variants for Mendelian diseases and are increasingly utilized in molecular and clinical genetics for diagnostic and counselling purposes. By contrast, genetic susceptibility for complex liver disorders is heterogeneous, as many different genes acting on multiple distinct pathways influence disease onset and severity. Risk variants for complex liver disorders are relatively common, typically of small effect size and detected by genome-wide association studies (GWAS), which compare the genetic variation of specific loci using thousands of patients and healthy controls. Thus far, GWAS have detected dozens of unique and overlapping risk alleles for complex liver disease, but these account for less than a quarter of the overall disease liability. These observations emphasize that environmental exposures on a background of genetic predisposition are significant drivers of liver pathophysiology. Rare variants of large effect size, undetectable by GWAS, may also affect the development of complex disease on a case-to-case basis but evidence for such a scenario remains to be determined. Conclusions: Genetic technologies have identified numerous risk genes for Mendelian and complex liver disorders transforming disease recognition. For complex liver disorders, deciphering the interplay between genetic risk and environment determinants remains a significant challenge for unlocking the development of novel and personalized interventions.
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Peyvandi, Flora, Tom Kunicki, and David Lillicrap. "Genetic sequence analysis of inherited bleeding diseases." Blood 122, no. 20 (November 14, 2013): 3423–31. http://dx.doi.org/10.1182/blood-2013-05-505511.
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Abstract The genes encoding the coagulation factor proteins were among the first human genes to be characterized over 25 years ago. Since then, significant progress has been made in the translational application of this information for the 2 commonest severe inherited bleeding disorders, hemophilia A and B. For these X-linked disorders, genetic characterization of the disease-causing mutations is now incorporated into the standard of care and genetic information is used for risk stratification of treatment complications. With electronic databases detailing >2100 unique mutations for hemophilia A and >1100 mutations for hemophilia B, these diseases are among the most extensively characterized inherited diseases in humans. Experience with the genetics of the rare bleeding disorders is, as expected, less well advanced. However, here again, electronic mutation databases have been developed and provide excellent guidance for the application of genetic analysis as a confirmatory approach to diagnosis. Most recently, progress has also been made in identifying the mutant loci in a variety of inherited platelet disorders, and these findings are beginning to be applied to the genetic diagnosis of these conditions. Investigation of patients with bleeding phenotypes without a diagnosis, using genome-wide strategies, may identify novel genes not previously recognized as playing a role in hemostasis.
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Olivares, Marta, J. Moisés Laparra, and Yolanda Sanz. "Host genotype, intestinal microbiota and inflammatory disorders." British Journal of Nutrition 109, S2 (January 29, 2013): S76—S80. http://dx.doi.org/10.1017/s0007114512005521.
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Intestinal microbiota may influence human physiology and disease risk due to the role it plays in mediating appropriate immune responses to harmful and innocuous antigens. Colonisation of the intestine in early life seems particularly important as it is the main environmental stimulus for immune system maturation. This is a dynamic process, which depends on both environmental and genetic factors. The pathogenesis of inflammatory bowel disease, such as Crohn's disease, involves genetic polymorphisms (e.g. CARD15/nucleotide-binding oligomerisation domain 2) related to an excessive inflammatory response to commensal microbiota and to its unbalanced composition. Atopic diseases have also been linked to imbalances in microbiota and to related genetic factors (e.g. TLR4 and CD14 genes), although these associations are still controversial. Research into the relationship between the genetic risk of developing celiac disease (human leukocyte antigen (HLA)-DQ2/DQ8) and the early colonisation process in infants at family risk of the disease has also reported that the HLA-DQ genotype could influence staphylococcal colonisation. Future observational studies considering both host genetics and microbiota could be critical in defining the complex host–microbe interactions and the respective role each plays in inflammatory disorders.
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Платонкина, Татьяна, Tatyana Platonkina, Лариса Боговин, Larisa Bogovin, Денис Наумов, Denis Naumov, Александр Овсянкин, and Aleksandr Ovsyankin. "GENETIC RESEARCHES OF DEPRESSIVE DISORDERS: LITERATURE REVIEW." Bulletin physiology and pathology of respiration 1, no. 68 (June 7, 2018): 96–106. http://dx.doi.org/10.12737/article_5b19ee7411be17.38016141.
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This work is devoted to the review of genetic researches in the field of etiology and development of depressive disorders. The interest to depression is caused by high prevalence and increasing frequency of this disease in the world and its negative influence on the ability to work and social activity of a man. Depression is a heterogenic disorder, in the pathogenesis of which both genetic factors and the conditions of micro-and macroenvironment play an important role. The study of polymorphisms of gene-candidates as well as consequences from the totaling of these effects can help to define the degree of disposition to depressive disorders. According to modern theories, a special role in pathogenesis and dynamics of depression belong to the pathology of molecular components of neurochemical structures of central nervous system and genes that code them. The most known genes, for which the correlation with anxiety, depression or their separate symptoms was found, are the genes of 5-serotonin transporters HIT, noradrenalin NET, dopamines DAT1 and D4DR, neurotropic brain factor BDHF, serotonin receptors of HTR1A, HTR2A, genes of enzymes of tryptophan hydroxylase TPH, catechol-O-methyl transferase COMT, methylene tetra hydro folate reductase MTHFR, genes of anti-inflammatory mediators IL-6, IL-1beta, TNF-a, CRP, genes participating in the immune response PSMB4 and TBX21, rare variants of gene NKPD1 and others. The study of the genetic background in relation with affective manifestations seems to be important and promising. In-time and accurate diagnosis of the disposition to depressive disorders can be the most important one in successful prophylactics and effective treatment of patients.
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Hinckley, Jesse, and Jorge Di Paola. "Genetic basis of congenital platelet disorders." Hematology 2014, no. 1 (December 5, 2014): 337–42. http://dx.doi.org/10.1182/asheducation-2014.1.337.
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Abstract Over the past 4 decades, a better understanding of the genetic origins of inherited platelet disorders has illuminated avenues of investigation in megakaryopoiesis and has identified targets of pharmacologic intervention. Many of these discoveries have been translated into clinical medicine. The success of inherited platelet disorder research is underpinned by broader advances in methodology through the biochemical and molecular revolution of the 20th and 21st centuries, respectively. Recently, modern genomics techniques have affected platelet and platelet disorders research, allowing for the discovery of several genes involved in platelet production and function and for a deeper understanding of the RNA and miRNA networks that govern platelet function. In this short review, we focus on recent developments in the genetic elucidation of several disorders of platelet number and in the molecular architecture that determines the “genetic makeup” of a platelet in health and disease.
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Wei, Siyang, Zilan Xin, and Yuankai Zhang. "Genetic and environment factors of mental disorders: Twin studies about Alzheimer’s disease, Phobia and Autism Spectrum Disorder." E3S Web of Conferences 292 (2021): 03062. http://dx.doi.org/10.1051/e3sconf/202129203062.
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With the natural and social environment changing, people’s mental health is facing severe challenges. Many people are suffering from mental disorders in the present day. A large part of mental disorders can be linked with the nerve system. And nerve system disorders tend to be associated with the development of nerve systems. The gene and the environment can play an important role in the development of the body, and abnormal genes and detrimental environmental factors can contribute a lot to nerve system disorders. Previous research has studied the occurrence and gene-and-environmental impact of many nerve system disorders. Among them, this essay chooses three kinds of disorders: Alzheimer’s disease (AD), Phobia, and Autism Spectrum Disorder, which can cause a lot of trouble in people’s daily life. In this essay, we are to study the occurrence of some nerve systems’ disorders and hope to study the genetic and environmental contribution of these disorders. These three disorders gain a lot of attention as they are very common, and they can partly reflect the contribution of genes and the environment.
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Mathis, Maria Alice de, Pedro de Alvarenga, Guilherme Funaro, Ricardo Cezar Torresan, Ivanil Moraes, Albina Rodrigues Torres, Monica L. Zilberman, and Ana Gabriela Hounie. "Gender differences in obsessive-compulsive disorder: a literature review." Revista Brasileira de Psiquiatria 33, no. 4 (December 2011): 390–99. http://dx.doi.org/10.1590/s1516-44462011000400014.
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INTRODUCTION: Obsessive-compulsive disorder (OCD) is a heterogeneous condition, in which subtypes have been proposed. Previous studies suggested that gender plays a relevant role in OCD phenotypic expression. This study aimed to review the literature on gender differences in clinical, genetic or familial aspects of OCD. METHOD: A conventional review was conducted, including all papers that investigated demographic, clinical, and genetic aspects of OCD according to gender. The search was based on data available in Medline and PsycINFO databases in the last 20 years, using as keywords: obsessive-compulsive disorder; and: gender, sex, male, female, demographic characteristics, clinical features, clinical characteristics, genetic, genes, genetics gender OCD, genes OCD, genes OCD males, genes OCD females. RESULTS: Sixty three of 487 phenotypical and genetics studies were selected. Most studies indicate that male patients are more likely than females to be single, present early onset of symptoms and chronic course of the disorder, greater social impairment, more sexual-religious and aggressive symptoms, and greater comorbidity with tic and substance use disorders. Female patients present more contamination/cleaning symptoms and greater comorbidity with eating and impulse-control disorders. Genetic and family studies are inconclusive, but suggest that gender may play a role in the disease expression. CONCLUSIONS: Gender is a relevant factor that should be taken into account when evaluating OCD patients. More studies are necessary to determine whether in fact it defines a homogeneous and particular group in OCD.
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Cortés, Jessica María Rodríguez, and Hugo Mendieta Zerón. "Genetics of Thyroid Disorders." Folia Medica 61, no. 2 (June 1, 2019): 172–79. http://dx.doi.org/10.2478/folmed-2018-0078.
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Abstract Background: Thyroid diseases are the most common endocrine pathologies second to diabetes. They have been shown to have high genetic impact, and variants in any of the genes involved in the metabolism of thyroid hormones have marked influence on the development of these diseases. Aim: To identify the genes that have been most involved in the development of thyroid pathologies by reviewing the literature with recent relevant articles. Materials and methods: We performed a literature search on the NCBI (National Center for Biotechnology Information) databases, and that of the European Bioinformatics Institute (EMBL-EBI) using keywords related to the topic of interest). Results: Activation of oncogenes such as RAS, BRAF, RET/PTC and the overstimulation of the PI3K/AKT pathway plays an important role in thyroid tumorigenesis. SLC5A5, SLC26A4, TG, TPO, DUOX2, DUOXA2 are related to hypothyroidism. Risk factors for Graves’ disease are associated with the presence of HLA-DR3, CTLA4, PTPN22, CD40, IL2RA (CD25), FCRL3, and IL23R. FOXE1 can be associated to hypothyroidism and papillary thyroid cancer. Conclusions: Thyroid diseases are polygenetic, and while there are sufficient pathways affected by genetic changes, and there is, to our knowledge, no gene that has been found to be specifically causal, and the pathology has been the result of the interaction of many genetic variables such as polymorphisms or mutations.
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Morato Torres, C. Alejandra, Zinah Wassouf, Faria Zafar, Danuta Sastre, Tiago Fleming Outeiro, and Birgitt Schüle. "The Role of Alpha-Synuclein and Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders." International Journal of Molecular Sciences 21, no. 16 (August 10, 2020): 5724. http://dx.doi.org/10.3390/ijms21165724.
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Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
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Stahl, Stephen M. "Fooling Mother Nature: Epigenetics and Novel Treatments for Psychiatric Disorders." CNS Spectrums 15, no. 6 (June 2010): 358–66. http://dx.doi.org/10.1017/s1092852900029229.
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Modern formulations of psychiatric disorders hypothesize that mother nature goes awry, causing both genetic and epigenetic disease actions. Genetic disease actions are the consequences of naturally inherited risk genes that have an altered sequence of DNA. This altered DNA sequence theoretically leads to the production of altered gene products in neurons, causing inefficient information processing in various brain circuits, and biasing those circuits towards developing symptoms of a mental illness. Epigenetic disease actions are theorized either to activate risk genes to make an altered gene product or to activate normal genes to make normal gene products but at the wrong time. Epigenetic disease mechanisms theoretically turn normal genes into risk genes by causing normal genes to be expressed in neurons when these genes should be silenced or by causing normal genes to be silenced when they should be expressed.
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Foreman, John. "Genetic Diseases of the Kidney." Open Urology & Nephrology Journal 8, no. 1 (November 26, 2015): 136–47. http://dx.doi.org/10.2174/1874303x015080100136.
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The number of genes associated with renal disease is increasing every day and this has led to a clearer understanding of the pathophysiology of renal disease in many disorders. It is also appreciated now that a genetic mutation(s) underlie many renal syndromes. Genetic testing may also offer the possibility to diagnose some renal diseases without the need for a renal biopsy. It also allows the prenatal diagnosis of certain renal diseases in at risk fetuses or identification of potential renal disease before it has become manifest. Finally, identification of a specific gene mutation holds the possibility of correction though gene therapy in the future. It is increasingly clear that many renal disorders in pediatrics are a consequence of genetic mutations. In the future, genetic testing will become as easy and as common as ordering a serum creatinine today.
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McGuffin, P. "Methodology of genetic research in psychiatry." Acta Neuropsychiatrica 11, no. 2 (June 1999): 45–47. http://dx.doi.org/10.1017/s0924270800036127.
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Most forms of behaviour whether normal or abnormal, show a tendency to run in families. However, these can range from symptoms of dementia and movement disorder caused by the comparatively rare autosomal dominant Huntington's disease to common everyday aspects of behaviour such as religious persuasion or career choice. Normal behaviours and most common disorders do not show simple mendelian inheritance but instead have more complex patterns of transmission involving either major genes with incomplete penetrance, multiple genes of small effect, or a combination of the two. In addition, common complex phenotypes usually involve the combination of genetic and environmental factors. Therefore once family studies have shown that a disorder or trait is familial the next stage is to perform twin studies and, if possible adoption studies to investigate whether this results from shared genes, shared environment or a combination of the two.
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Souery, D., and J. Mendlewicz. "Molecular genetic findings in mood disorders." Acta Neuropsychiatrica 11, no. 2 (June 1999): 67–70. http://dx.doi.org/10.1017/s092427080003619x.
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Traditional methods used to asses genetic effects, such as twins, adoption and family studies, have demonstrated the role genetic vulnerability factors in the etiology of major psychiatric diseases such as affective disorders and schizophrenia. It remains however impossible, using these methods, to specify the genetic variables involved and the exact mode of transmission of these diseases. New genetic approaches in psychiatry include the use of DNA markers in sophisticated strategies to examine families and populations. Genetic linkage (in families) and allelic association (in unrelated subjects) are the most frequent techniques applied searching for genes in psychiatric diseases. Advances in these methods have permitted their application to complex diseases in which the mode of genetic transmission is unknown. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome, specific hypotheses such as mutations have also, been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of affective disorders. Large multi-centre and multi-disciplinary projects are currently underway in Europe and in the US and hopefully will improve our understanding of the genetic factors involved in affective disorders. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption and family studies, have been improved, providing validated models to test the gene-environment interactions.
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Zhang, Pei-Lan, Yan Chen, Chen-Hao Zhang, Yu-Xin Wang, and Pedro Fernandez-Funez. "Genetics of Parkinson’s disease and related disorders." Journal of Medical Genetics 55, no. 2 (November 18, 2017): 73–80. http://dx.doi.org/10.1136/jmedgenet-2017-105047.
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Parkinson’s disease (PD) is a complex and heterogeneous neurological condition characterised mainly by bradykinesia, resting tremor, rigidity and postural instability, symptoms that together comprise the parkinsonian syndrome. Non-motor symptoms preceding and following clinical onset are also helpful diagnostic markers revealing a widespread and progressive pathology. Many other neurological conditions also include parkinsonism as primary or secondary symptom, confounding their diagnosis and treatment. Although overall disease course and end-stage pathological examination single out these conditions, the significant overlaps suggest that they are part of a continuous disease spectrum. Recent genetic discoveries support this idea because mutations in a few genes (α-synuclein, LRRK2, tau) can cause partially overlapping pathologies. Additionally, mutations in causative genes and environmental toxins identify protein homeostasis and the mitochondria as key mediators of degeneration of dopaminergic circuits in the basal ganglia. The evolving mechanistic insight into the pathophysiology of PD and related conditions will contribute to the development of targeted and effective symptomatic treatments into disease-modifying therapies that will reduce the burden of these dreadful conditions.
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Szyfter, Krzysztof, Wojciech Gawęcki, and Witold Szyfter. "Genetic background of Meniere’s disease." Journal of Medical Science 87, no. 3 (October 3, 2018): 158–61. http://dx.doi.org/10.20883/jms.2018.289.
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Meniere’s disease (MD) as an inner ear disorder including such symptoms as recurrent vertigo attacks, tinnitus, fluctuating or progressive sensorineural hearing loss. Its relatively frequent familial incidence implicates a genetic background. An autosomal dominant inheritance was commonly observed with a few exceptions. It was established that Meniere’s disease is not a monogenic disorder. Instead a group of genes of genomic and mitochondrial genes was established as determinants of hearing loss. Another group of genes was associated with inner ear (vestibulum, labyrinth, endolymph) alterations followed by dizziness and tinnitus. Altogether, many studies suggest a multigenic interaction to predispose to develop Meniere’s disease.
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Papale, Maria, Giuseppe Fabio Parisi, Amelia Licari, Raffaella Nenna, and Salvatore Leonardi. "Genetic Disorders of Surfactant Deficiency and Neonatal Lung Disease." Current Respiratory Medicine Reviews 15, no. 3 (January 1, 2020): 210–20. http://dx.doi.org/10.2174/1573398x15666191022101620.
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Pulmonary surfactant is a heterogeneous combination of lipids and proteins, which prevents alveolar collapse at the end of expiration cycle by decreasing the alveolar surface tension at the air-liquid interface. At birth, the expression of surfactant is very important for normal lung function and it is strictly correlated to gestational age. The best known genetic mutations associated with the onset of respiratory distress in preterm and full-term newborns and with interstitial lung disease later in childhood are those involving the phospholipid transporter (ABCA3) or surfactant proteins C and B (SP-C and SP-B) genes. In particular, mutations in the SP-B gene induce respiratory distress in neonatal period, while alterations on gene encoding for SP-C are commonly associated with diffuse lung disease in children or in adults. Both clinical phenotypes are present, if genetic mutations interest even the phospholipid transporter ABCA3 ambiguity in the sentence. Interstitial lung disease in children (chILD) is defined as a mixed category of mainly chronic and rare respiratory disorders with increased mortality and morbidity. Although genetic alterations are mainly responsible for the onset of these diseases, however, there are also other pathogenic factors that contribute to increase the severity of clinical presentation. In this review, we analyze all clinical features of these rare pulmonary diseases in neonatal and in pediatric age.
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Makaram, Navnit S., and Stuart H. Ralston. "Genetic Determinants of Paget’s Disease of Bone." Current Osteoporosis Reports 19, no. 3 (May 14, 2021): 327–37. http://dx.doi.org/10.1007/s11914-021-00676-w.
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Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.
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Bralten, Janita, Nina R. Mota, Cornelius J. H. M. Klemann, Ward De Witte, Emma Laing, David A. Collier, Hilde de Kluiver, et al. "Genetic underpinnings of sociability in the general population." Neuropsychopharmacology 46, no. 9 (May 30, 2021): 1627–34. http://dx.doi.org/10.1038/s41386-021-01044-z.
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AbstractLevels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h2 of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits—loneliness and social anxiety—but not with bipolar disorder or Alzheimer’s disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.
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Pinheiro, Andréa Poyastro, Patrick F. Sullivan, Josue Bacaltchuck, Pedro Antonio Schmidt do Prado-Lima, and Cynthia M. Bulik. "Genetics in eating disorders: extending the boundaries of research." Revista Brasileira de Psiquiatria 28, no. 3 (August 9, 2006): 218–25. http://dx.doi.org/10.1590/s1516-44462006005000004.
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OBJECTIVE: To review the recent literature relevant to genetic research in eating disorders and to discuss unique issues which are crucial for the development of a genetic research project in eating disorders in Brazil. METHOD: A computer literature review was conducted in the Medline database between 1984 and may 2005 with the search terms "eating disorders", "anorexia nervosa", "bulimia nervosa", "binge eating disorder", "family", "twin" and "molecular genetic" studies. RESULTS: Current research findings suggest a substantial influence of genetic factors on the liability to anorexia nervosa and bulimia nervosa. Genetic research with admixed populations should take into consideration sample size, density of genotyping and population stratification. Through admixture mapping it is possible to study the genetic structure of admixed human populations to localize genes that underlie ethnic variation in diseases or traits of interest. CONCLUSIONS: The development of a major collaborative genetics initiative of eating disorders in Brazil and South America would represent a realistic possibility of studying the genetics of eating disorders in the context of inter ethnic groups, and also integrate a new perspective on the biological etiology of eating disorders.
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Ginsburg, David. "Genetic Modifiers of Thrombosis in Mice." Blood 114, no. 22 (November 20, 2009): SCI—44—SCI—44. http://dx.doi.org/10.1182/blood.v114.22.sci-44.sci-44.
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Abstract Abstract SCI-44 The genetic factors responsible for the highly variable clinical course of inherited bleeding disorders including von Willebrand disease and hemophilia are largely unknown. Similar factors are also likely to contribute to the variability of common thrombotic disorders, including factor V Leiden. Studies by our lab over the past 10 years have used the power of mouse genetics to identify genes contributing to this variability (referred to as ‘modifier‘ genes). By performing genetic crosses between inbred strains of mice with elevated plasma levels of von Willebrand Factor (VWF) and other strains with low levels, we have mapped a total of 6 genetic factors contributing to the control of murine plasma VWF levels. Similar studies in ADAMTS13-deficient mice are in progress aimed at characterizing genes modifying susceptibility thrombotic thrombocytopenic purpura. We have also conducted large scale mutagenesis studies in the mouse in an effort to identify larger numbers of genes contributing to thrombosis risk in the setting of Factor V Leiden, and most recently are extending this approach to similar genetic screens in zebrafish. Finally, recent advances in human genetics are expanding the potential opportunities for directly identifying bleeding and thrombosis modifier genes in humans. Disclosures No relevant conflicts of interest to declare.
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Forés-Martos, Jaume, Cesar Boullosa, David Rodrigo-Domínguez, Jon Sánchez-Valle, Beatriz Suay-García, Joan Climent, Antonio Falcó, et al. "Transcriptomic and Genetic Associations between Alzheimer’s Disease, Parkinson’s Disease, and Cancer." Cancers 13, no. 12 (June 15, 2021): 2990. http://dx.doi.org/10.3390/cancers13122990.
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Alzheimer’s (AD) and Parkinson’s diseases (PD) are the two most prevalent neurodegenerative disorders in human populations. Epidemiological studies have shown that patients suffering from either condition present a reduced overall risk of cancer than controls (i.e., inverse comorbidity), suggesting that neurodegeneration provides a protective effect against cancer. Reduced risks of several site-specific tumors, including colorectal, lung, and prostate cancers, have also been observed in AD and PD. By contrast, an increased risk of melanoma has been described in PD patients (i.e., direct comorbidity). Therefore, a fundamental question to address is whether these associations are due to shared genetic and molecular factors or are explained by other phenomena, such as flaws in epidemiological studies, exposure to shared risk factors, or the effect of medications. To this end, we first evaluated the transcriptomes of AD and PD post-mortem brain tissues derived from the hippocampus and the substantia nigra and analyzed their similarities to those of a large panel of 22 site-specific cancers, which were obtained through differential gene expression meta-analyses of array-based studies available in public repositories. Genes and pathways that were deregulated in both disorders in each analyzed pair were examined. Second, we assessed potential genetic links between AD, PD, and the selected cancers by establishing interactome-based overlaps of genes previously linked to each disorder. Then, their genetic correlations were computed using cross-trait LD score regression and GWAS summary statistics data. Finally, the potential role of medications in the reported comorbidities was assessed by comparing disease-specific differential gene expression profiles to an extensive collection of differential gene expression signatures generated by exposing cell lines to drugs indicated for AD, PD, and cancer treatment (LINCS L1000). We identified significant inverse associations of transcriptomic deregulation between AD hippocampal tissues and breast, lung, liver, and prostate cancers, and between PD substantia nigra tissues and breast, lung, and prostate cancers. Moreover, significant direct (same direction) associations of deregulation were observed between AD and PD and brain and thyroid cancers, as well as between PD and kidney cancer. Several biological processes, including the immune system, oxidative phosphorylation, PI3K/AKT/mTOR signaling, and the cell cycle, were found to be deregulated in both cancer and neurodegenerative disorders. Significant genetic correlations were found between PD and melanoma and prostate cancers. Several drugs indicated for the treatment of neurodegenerative disorders and cancer, such as galantamine, selegiline, exemestane, and estradiol, were identified as potential modulators of the comorbidities observed between neurodegeneration and cancer.
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Dallapiccola, B., I. Torrente, R. Mingarelli, and G. Novelli. "From Genetic Research into Clinical Practice." Acta geneticae medicae et gemellologiae: twin research 46, no. 3 (July 1997): 139–46. http://dx.doi.org/10.1017/s0001566000000556.
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AbstractThe present genome era is characterized by speedy progress and prompt transfer of results into clinical practice. This creates the need for rapid disclosure of results and renewal of laboratory's protocols. Molecular cytogenetics has provided and increased ability to identify chromosomes, correlate chromosome structure with gene location, find out cryptic aberrations, and detect specific DNA sequences. These advances have allowed the confident discovery of a number of contiguous gene syndromes. The positional cloning and positional candidate strategies have greatly expedited the search process of disease genes, and become relevant methods for genes' discovery. Understanding the molecular basis of diseases has shown an unpredicted wide genetic heterogeneity, which has splitted single disorders into many clinically similar conditions, and added complexity to the nosology of human diseases. The opposite process, allelism, where clinical diversity results from allelic mutations, has lumped together many distinct disorders, by showing that different clinical entities are not necessarily due to mutations in different genes. Dynamic mutations have provided the molecular understanding of interindividual and intrafamilial variability including anticipation, in a number of diseases. The discovery of distinct correlations between the molecular pattern and disease severity is providing a unique opportunity for using molecular results to assess the clinical outcome. Diagnostic, presymptomatic and predictive molecular testing are becoming widely used and provide enormous opportunities for improving the lot of our patients.
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Mencacci, Niccolò E., Regina Reynolds, Sonia Garcia Ruiz, Jana Vandrovcova, Paola Forabosco, Alvaro Sánchez-Ferrer, Viola Volpato, et al. "Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders." Brain 143, no. 9 (August 21, 2020): 2771–87. http://dx.doi.org/10.1093/brain/awaa217.
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Abstract Dystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities, including anxiety, depression, obsessive-compulsive disorder and schizophrenia, are frequent in patients with dystonia. While mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia, the cellular, anatomical, and molecular basis remains unknown for most genetic forms of dystonia, as does its genetic and biological relationship to neuropsychiatric disorders. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. To determine the cellular specificity of dystonia-associated genes in the brain, single-nuclear transcriptomic data derived from mouse brain was used together with expression-weighted cell-type enrichment. To identify functional relationships among dystonia-associated genes, we determined the enrichment of these genes in co-expression networks constructed from 10 human brain regions. Stratified linkage-disequilibrium score regression was used to test whether co-expression modules enriched for dystonia-associated genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson’s disease. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons. Furthermore, 4 of 220 gene co-expression modules tested were significantly enriched for the dystonia-associated genes. The identified modules were derived from the substantia nigra, putamen, frontal cortex, and white matter, and were all significantly enriched for genes associated with synaptic function. Finally, we demonstrate significant enrichments of the heritability of major depressive disorder, obsessive-compulsive disorder and schizophrenia within the putamen and white matter modules, and a significant enrichment of the heritability of Parkinson’s disease within the substantia nigra module. In conclusion, multiple dystonia-associated genes interact and contribute to pathogenesis likely through dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons and frontal cortical neurons. Furthermore, the enrichment of the heritability of psychiatric disorders in the co-expression modules enriched for dystonia-associated genes indicates that psychiatric symptoms associated with dystonia are likely to be intrinsic to its pathophysiology.
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Crisafulli, C. "Inflammation and Pruning May Inform Risk to Psychiatric Disorders. Lessons From Large Genetic Data." European Psychiatry 41, S1 (April 2017): S56. http://dx.doi.org/10.1016/j.eurpsy.2017.01.034.
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BackgroundIt's known that psychiatric disorders are caused to either environmental and genetics factors. Through the years several hypotheses were tested and many genes were screened for association, resulting in a huge amount of data available for the scientific community. Despite that, the molecular mechanics behind psychiatric disorders remains largely unknown. Traditional association studies may be not enough to pinpoint the molecular underpinnings of psychiatric disorder. We tried to applying a methodology that investigates molecular-pathway-analysis that takes into account several genes per time, clustered in consistent molecular groups and may successfully capture the signal of a number of genetic variations with a small single effect on the disease. This approach might reveal more of the molecular basis of psychiatric disorders.Methodsi)We collected data on studies available in literature for the studied disorder (e.g. Schizophrenia, Bipolar Disorder);ii)We extracted a pool of genes that are likely involved with the disease;iii)We used these genes as starting point to map molecular cascades function-linked. The molecular cascades are then analyzed and pathways and sub-pathways, possibly involved with them, are identified and tested for association.Results/discussionWe obtained interesting results. In particular, signals of enrichment (association) were obtained multiple times on the molecular pathway associated with the pruning activity and inflammation. Molecular mechanics related to neuronal pruning were focused as a major and new hypothesis for the pathophysiology of psychiatric disorders and the role of inflammatory events has been extensively investigated in psychiatry. intersting, inflammatory mechanics in the brain may also play a role in neuronal pruning during the early development of CNS.Disclosure of interestThe author has not supplied his declaration of competing interest.
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Cuppari, Caterina, Maria Concetta Cutrupi, Annamaria Salpietro, Alessia Sallemi, Monica Fusco, Giuseppe Fabio Parisi, and Carmelo Salpietro. "Genetic Anomalies of the Respiratory Tract." Current Respiratory Medicine Reviews 15, no. 3 (January 1, 2020): 221–30. http://dx.doi.org/10.2174/1573398x15666191022100525.
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Hereditary lung diseases can affect the airways, parenchyma and vasculature of the lung. Such diseases comprehend simple monogenic disorders such as Kartagener syndrome and α1-antitrypsin deficiency, in which mutations of critical genes are sufficient to induce well‐defined disease phenotypes. A major comprehension of the genetic basis of pulmonary diseases has produced new investigations into their underlying pathophysiology and contributed sometimes to clarify on more frequent sporadic forms. The presence of these structural abnormalities of the respiratory tract can be fatal, so that the identification of causative genes has allowed prenatal diagnosis for many diseases giving a greater hope of survival thanks to a more adequate and prompt management.
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Keogh, Michael J., Wei Wei, Juvid Aryaman, Ian Wilson, Kevin Talbot, Martin R. Turner, Chris-Anne McKenzie, et al. "Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 8 (January 13, 2018): 813–16. http://dx.doi.org/10.1136/jnnp-2017-317234.
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BackgroundSeveral studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.MethodsWe analysed 980 neuropathologically characterised human brains with Alzheimer’s disease (AD), Parkinson’s disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as ‘oligogenic’.ResultsThe majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls.ConclusionsA priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.
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Pierzynowska, Karolina, Lidia Gaffke, Magdalena Podlacha, and Grzegorz Węgrzyn. "Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies." International Journal of Molecular Sciences 21, no. 3 (February 10, 2020): 1156. http://dx.doi.org/10.3390/ijms21031156.
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Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their accumulation in cells. Among 11 known types and subtypes of MPS, neuronopathy occurs in seven (MPS I, II, IIIA, IIIB, IIIC, IIID, VII). Brain dysfunctions, occurring in these seven types/subtypes include various behavioral disorders. Intriguingly, behavioral symptoms are significantly different between patients suffering from various MPS types. Molecular base of such differences remains unknown. Here, we asked if expression of genes considered as connected to behavior (based on Gene Ontology, GO terms) is changed in MPS. Using cell lines of all MPS types, we have performed transcriptomic (RNA-seq) studies and assessed expression of genes involved in behavior. We found significant differences between MPS types in this regard, with the most severe changes in MPS IIIA (the type considered as the behaviorally most severely affected), while the lowest changes in MPS IVA and MPS VI (types in which little or no behavioral disorders are known). Intriguingly, relatively severe changes were found also in MPS IVB (in which, despite no behavioral disorder noted, the same gene is mutated as in GM1 gangliosidosis, a severe neurodegenerative disease) and MPS IX (in which only a few patients were described to date, thus, behavioral problems are not well recognized). More detailed analyses of expression of certain genes allowed us to propose an association of specific changes in the levels of transcripts in specific MPS types to certain behavioral disorders observed in patients. Therefore, this work provides a principle for further studies on the molecular mechanism of behavioral changes occurring in MPS patients.
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Baird, Denis A., Jimmy Z. Liu, Jie Zheng, Solveig K. Sieberts, Thanneer Perumal, Benjamin Elsworth, Tom G. Richardson, et al. "Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome." PLOS Genetics 17, no. 1 (January 8, 2021): e1009224. http://dx.doi.org/10.1371/journal.pgen.1009224.
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Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer’s Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer’s disease, 6 genes with Parkinson’s disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.
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Baird, Denis A., Jimmy Z. Liu, Jie Zheng, Solveig K. Sieberts, Thanneer Perumal, Benjamin Elsworth, Tom G. Richardson, et al. "Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome." PLOS Genetics 17, no. 1 (January 8, 2021): e1009224. http://dx.doi.org/10.1371/journal.pgen.1009224.
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Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer’s Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer’s disease, 6 genes with Parkinson’s disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.
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Levy, Amanda M., Peristera Paschou, and Zeynep Tümer. "Candidate Genes and Pathways Associated with Gilles de la Tourette Syndrome—Where Are We?" Genes 12, no. 9 (August 26, 2021): 1321. http://dx.doi.org/10.3390/genes12091321.
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Gilles de la Tourette syndrome (GTS) is a childhood-onset neurodevelopmental and -psychiatric tic-disorder of complex etiology which is often comorbid with obsessive-compulsive disorder (OCD) and/or attention deficit hyperactivity disorder (ADHD). Twin and family studies of GTS individuals have shown a high level of heritability suggesting, that genetic risk factors play an important role in disease etiology. However, the identification of major GTS susceptibility genes has been challenging, presumably due to the complex interplay between several genetic factors and environmental influences, low penetrance of each individual factor, genetic diversity in populations, and the presence of comorbid disorders. To understand the genetic components of GTS etiopathology, we conducted an extensive review of the literature, compiling the candidate susceptibility genes identified through various genetic approaches. Even though several strong candidate genes have hitherto been identified, none of these have turned out to be major susceptibility genes yet.
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Marcuzzi, Annalisa, Anna Monica Bianco, Martina Girardelli, Alberto Tommasini, Stefano Martelossi, Lorenzo Monasta, and Sergio Crovella. "Genetic and Functional Profiling of Crohn's Disease: Autophagy Mechanism and Susceptibility to Infectious Diseases." BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/297501.
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Crohn's disease is a complex disease in which genome, microbiome, and environment interact to produce the immunological background of the disease. Disease in childhood is more extensive and characterized by a rapid progression, leading to severe repercussions in the course of the disorder. Several genetic variations have been associated with an increased risk of developing the disease and most of these are also implicated in other autoimmune disorders. The gut has many tiers of defense against incursion by luminal microbes, including the epithelial barrier and the innate and adaptive immune responses. Moreover, recent evidence shows that bacterial and viral infections, as well as inflammasome genes and genes involved in the autophagy process, are implicated in Crohn's disease pathogenesis. The aim of this review is to establish how much the diagnostic system can improve, thus increasing the success of Crohn's disease diagnosis. The major expectation for the near future is to be able to anticipate the possible consequences of the disease already in childhood, thus preventing associated complications, and to choose the best treatment for each patient.
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Asatryan, Babken, and Argelia Medeiros-Domingo. "Molecular and genetic insights into progressive cardiac conduction disease." EP Europace 21, no. 8 (April 26, 2019): 1145–58. http://dx.doi.org/10.1093/europace/euz109.
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Abstract Progressive cardiac conduction disease (PCCD) is often a primarily genetic disorder, with clinical and genetic overlaps with other inherited cardiac and metabolic diseases. A number of genes have been implicated in PCCD pathogenesis with or without structural heart disease or systemic manifestations. Precise genetic diagnosis contributes to risk stratification, better selection of specific therapy and allows familiar cascade screening. Cardiologists should be aware of the different phenotypes emerging from different gene-mutations and the potential risk of sudden cardiac death. Genetic forms of PCCD often overlap or coexist with other inherited heart diseases or manifest in the context of multisystem syndromes. Despite the significant advances in the knowledge of the genetic architecture of PCCD and overlapping diseases, in a measurable fraction of PCCD cases, including in familial clustering of disease, investigations of known cardiac disease-associated genes fail to reveal the underlying substrate, suggesting that new causal genes are yet to be discovered. Here, we provide insight into genetics and molecular mechanisms of PCCD and related diseases. We also highlight the phenotypic overlaps of PCCD with other inherited cardiac and metabolic diseases, present unmet challenges in clinical practice, and summarize the available therapeutic options for affected patients.
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Labat-de-Hoz, Leticia, and Miguel A. Alonso. "Formins in Human Disease." Cells 10, no. 10 (September 27, 2021): 2554. http://dx.doi.org/10.3390/cells10102554.
Full textAbstract:
Almost 25 years have passed since a mutation of a formin gene, DIAPH1, was identified as being responsible for a human inherited disorder: a form of sensorineural hearing loss. Since then, our knowledge of the links between formins and disease has deepened considerably. Mutations of DIAPH1 and six other formin genes (DAAM2, DIAPH2, DIAPH3, FMN2, INF2 and FHOD3) have been identified as the genetic cause of a variety of inherited human disorders, including intellectual disability, renal disease, peripheral neuropathy, thrombocytopenia, primary ovarian insufficiency, hearing loss and cardiomyopathy. In addition, alterations in formin genes have been associated with a variety of pathological conditions, including developmental defects affecting the heart, nervous system and kidney, aging-related diseases, and cancer. This review summarizes the most recent discoveries about the involvement of formin alterations in monogenic disorders and other human pathological conditions, especially cancer, with which they have been associated. In vitro results and experiments in modified animal models are discussed. Finally, we outline the directions for future research in this field.
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Gadoury-Levesque, Vanessa, Lei Dong, Rui Su, Jianjun Chen, Kejian Zhang, Kimberly A. Risma, Rebecca A. Marsh, and Miao Sun. "Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders." Blood Advances 4, no. 12 (June 15, 2020): 2578–94. http://dx.doi.org/10.1182/bloodadvances.2020001605.
Full textAbstract:
Abstract This article explores the distribution and mutation spectrum of potential disease-causing genetic variants in hemophagocytic lymphohistiocytosis (HLH)–associated genes observed in a large tertiary clinical referral laboratory. Samples from 1892 patients submitted for HLH genetic analysis were studied between September 2013 and June 2018 using a targeted next-generation sequencing panel approach. Patients ranged in age from 1 day to 78 years. Analysis included 15 genes associated with HLH. A potentially causal genetic finding was observed in 227 (12.0%) samples in this cohort. A total of 197 patients (10.4%) had a definite genetic diagnosis. Patients with pathogenic variants in familial HLH genes tended to be diagnosed significantly younger compared with other genes. Pathogenic or likely pathogenic variants in the PRF1 gene were the most frequent. However, mutations in genes associated with degranulation defects (STXBP2, UNC13D, RAB27A, LYST, and STX11) were more common than previously appreciated and collectively represented >50% of cases. X-linked conditions (XIAP, SH2D1A, and MAGT1) accounted for 17.8% of the 197 cases. Pathogenic variants in the SLC7A7 gene were the least encountered. These results describe the largest cohort of genetic variation associated with suspected HLH in North America. Merely 10.4% of patients were identified with a clearly genetic cause by this diagnostic approach; other possible etiologies of HLH should be investigated. These results suggest that careful thought should be given regarding whether patients have a clinical phenotype most consistent with HLH vs other clinical and disease phenotypes. The gene panel identified known pathogenic and novel variants in 10 HLH-associated genes.
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Tsai, Yu-Young, Chun-Hao Su, and Woan-Yuh Tarn. "p53 Activation in Genetic Disorders: Different Routes to the Same Destination." International Journal of Molecular Sciences 22, no. 17 (August 27, 2021): 9307. http://dx.doi.org/10.3390/ijms22179307.
Full textAbstract:
The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.
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Futreal, Andy. "The Mutational Profile of Plasma Cell Disorders." Blood 122, no. 21 (November 15, 2013): SCI—14—SCI—14. http://dx.doi.org/10.1182/blood.v122.21.sci-14.sci-14.
Full textAbstract:
Abstract Multiple myeloma is a plasma cell malignancy that is the second most common hematologic cancer. The genetics of the disease have been previously characterized by two major subtypes involving recurrent translocations of the immunoglobulin heavy chain, c-MAF, cyclin D (CCND1) and FGFR3/MMSET oncogenes, and the hyperdiploid group with multiple recurrent trisomies. Further, there are characterized cytogenetic/ploidy subsets that appear to carry prognostic significance. Specifically, gains of chromosomes 5, 9, 11, 15, and 19 confer a good prognosis whilst gain of 1q plus deletions of 1p, 12p, 14q, 16q, and 22q confer a poor prognosis. More recently the application of massively parallel sequencing has revealed further insights into the genetic architecture of multiple myeloma. Work from several groups has identified the contribution of mutations in genes involved in non-canonical NF-kB signaling, MAPK signaling and histone methylation, as well as infrequent mutation of cancer genes implicated in other tumor types and novel genes. These data will be presented to give an overall update on the current state of multiple myeloma genetics and our current level of insight in the genomic complexity that characterizes this disease. Disclosures: No relevant conflicts of interest to declare.
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Rutter, Michael. "Nature, nurture, and psychopathology: A new look at an old topic." Development and Psychopathology 3, no. 2 (April 1991): 125–36. http://dx.doi.org/10.1017/s0954579400000031.
Full textAbstract:
AbstractThe important implications for developmental psychopathology that derive from advances in psychiatric and behavioral genetics are discussed in relation to a series of mistaken stereotypes: that strong effects mean that environmental influences must be unimportant; that genes provide a limit to potential; that genetic strategies are of no value for studying environmental influences; that nature and nurture are separate; that genes for serious diseases are necessarily bad; that diseases have nothing to do with normal variation; that genetic findings will not help identify diseases; that genetic influences diminish with age; that disorders that run in families must be genetic; that disorders that seem not to run in families cannot be genetic; and that single major genes lead only to specific rare diseases that follow a Mendelian pattern. The reasons why these stereotypes are mistaken are considered in relation to genetic concepts and findings.
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Rutter, Michael. "Nature, nurture, and psychopathology: A new look at an old topic." Development and Psychopathology 3, no. 2 (April 1991): 125–36. http://dx.doi.org/10.1017/s0954579400005198.
Full textAbstract:
AbstractThe important implications for developmental psychopathology that derive from advances in psychiatric and behavioral genetics are discussed in relation to a series of mistaken stereotypes: that strong effects mean that environmental influences must be unimportant; that genes provide a limit to potential; that genetic strategies are of no value for studying environmental influences; that nature and nurture are separate; that genes for serious diseases are necessarily bad; that diseases have nothing to do with normal variation; that genetic findings will not help identify diseases; that genetic influences diminish with age; that disorders that run in families must be genetic; that disorders that seem not to run in families cannot be genetic; and that single major genes lead only to specific rare diseases that follow a Mendelian pattern. The reasons why these stereotypes are mistaken are considered in relation to genetic concepts and findings.