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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
Monogenic diseases are the simplest genetic disorders to study as they tend to follow Mendelian genetics. Dominant and recessive diseases have characteristic patterns of inheritance (Figure 2.10). Dominant traits require only one defective copy to generate a disease phenotype. In contrast, recessive disorders are only visible when both copies of a gene are mutated. Recessive disorders often result from a loss in biological activity for the relevant protein. Sex linkage alters Mendelian genetics, as males carry only one copy of the X chromosome; recessive mutations carried on this chromosome behave as if dominant in men, while heterozygous females act as asymptomatic ‘carriers’. Polygenic disorders have a known genetic component (such as type 1 diabetes) but involve many genes and often environmental factors too (Table 2.1). In such cases, disease results from a combination of multiple polymorphisms, acting in concert with external factors. The risk of disease conveyed by each individual genetic variant in a polygenic disorder is relatively low and much lower than that conveyed by a genetic mutation in a monogenic disorder.
Preimplantation Genetic Testing for Polygenic Disorders
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Nathan R. Treff, Diego Marin, Laurent C. A. M. Tellier
Several studies have demonstrated that current polygenic disease risk scoring, from DNA alone, can identify individuals at risk equivalent to monogenic disorder risk (3,5,20). Given the determination that reproductive liberty ethically allows for PGT of adult-onset conditions (32), and the significant relative disease risk reduction achieved with PGT-P (27), patients without infertility may begin to consider utilization of IVF and PGT-P in a manner similar to the application of PGT-M. Evidence of utility in the general population has also been established by evaluating risk reduction from sibling selection within a large and relatively healthy cohort (27). Current application of PGT-P has primarily focused on providing additional embryo selection options for couples already undergoing IVF to treat infertility. Infertility itself represents an indication for PGT-P, given that patients with infertility have a higher risk of cancer, diabetes, and heart disease when compared to the general population (33).
Precision Medicine
Published in Paul Cerrato, John Halamka, Reinventing Clinical Decision Support, 2020
An in-depth discussion of the technological issues involved in importing genomic data into EHRs is beyond the scope of this book; however, several investigators are studying whether primary care physicians can manage this data once it’s available. In one pilot study, physicians were given access to one group of patients’ family history along with whole genome-sequencing reports that had previously been reviewed by genetic experts; a second group only provided a family history report to their physician.5 The genetic reports included monogenic disease risk (MDR) results, risk estimates for cardiometabolic traits, and pharmacogenomic associations. Eleven of the patients whose family history and genomic data were available had a risk of developing a monogenic disorder (22% of the 50 healthy patients in the first group), two of which had evidence of clinical disease. Geneticists rated the physicians’ management of monogenic disease risk information as appropriate in 8 patients (73%) and inappropriate in 2 cases (18%).
Alpha-1 antitrypsin deficiency: current therapy and emerging targets
Published in Expert Review of Respiratory Medicine, 2023
Oisín F. McElvaney, Daniel D. Fraughen, Oliver J. McElvaney, Tomás P. Carroll, Noel G. McElvaney
As AATD is a monogenic disorder, gene therapy would seem to provide a potential therapeutic option. The most commonly employed gene-delivery vector to date is the adeno associated virus (AAV), a single stranded DNA virus which can infect a variety of cells with low immunogenicity and stable long term expression. In the first human study in AATD, an AAV vector containing the AAT cDNA was administered intramuscularly. The level of AAT achieved was well below the putative protective threshold (PPT). Patients developed neutralizing antibodies against the AAV capsid but the expression lasted for up to one year [72]. A subsequent trial using a herpes-simplex virus-1 helper system showed a 10-fold higher level compared to the first trial but AAT levels remained below the PPT. This study required multiple intramuscular injections. Subsequent evaluation showed sustained AAT transgene expression of around 3% of the PPT with other downstream effects consistent with an increased antiprotease screen in blood [73].
High Prevalence of Anemia and Inherited Hemoglobin Disorders in Tribal Populations of Madhya Pradesh State, India
Published in Hemoglobin, 2020
Sonam Chourasia, Ravindra Kumar, Mendi P.S.S. Singh, Chandrika Vishwakarma, Ashok K. Gupta, Rajasubramaniam Shanmugam
Being a monogenic disorder, these Hb disorders can be prevented by premarital screening followed by genetic counseling for avoidance of marriages between carriers or possibility of prenatal diagnosis (PND). Several states have recently started community-wide screening programs for sickle cell disease and thalassemia in concordance with the government of India guidelines. In the past three decades, the Indian Council of Medical Research-National Institute of Research in Tribal Health (ICMR-NIRTH), has carried out prevalence studies in many tribal districts. Based on their input, the Madhya Pradesh Government initiated a targeted screening program in Tribal schools in the state. To coincide with this program, ICMR-NIRTH also carried out community-wide screening of hemoglobinopathies in three tribal districts: Dindori, Chhindwara, and Mandla.
Recent advances in screening and diagnosis of hemoglobinopathy
Published in Expert Review of Hematology, 2020
Kanjaksha Ghosh, Kinjalka Ghosh, Reepa Agrawal, Anita H. Nadkarni
For referral centers, Sanger sequencing (Figure 2(e)) [25] next-generation sequencing [26] should be available. Similarly, large deletions can be detected by GAP PCR (Figure 2(d)) or MLPA techniques (Figure 2(f)) [25] and also should be available in referral centers. Next-generation sequencing with continuously improving software will allow ones to predict the results of various gene–gene interaction in predicting the outcome of the natural history of hemoglobinopathy in a given patient and help us in tailor making his management. For example, we know that co-inheritance of alpha-thalassemia genes and various genetic polymorphisms in various locations of human genome controlling the expression of fetal hemoglobin modulates the severity of sickle cell anemia. Hence, knowing these polymorphisms/mutations, etc., across the genome and use of proper software/artificial intelligence will allow us to predict more accurately the heterogenous behavior of this monogenic disorder.