Advances In Medical Genetics Research Articles

Political-organisational aspects for the prevention of genetic diseases

The explosive advances in medical genetics are, as is well known, very recent, but they already constitute major references in the preparation of the new models of health action postulated by the establishment of the national health service. They have made possible and at the same time necessitated extensive legislative and organisational design work for the prevention, diagnosis and treatment of genetic diseases. Translated with DeepL.com (free version)

Recent Advances in Medical Genetics

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Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions.

Thoracic aortopathy–aneurysm, dissection, and rupture–is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway.

Genetics and genomic medicine in Iran.

Attention has been focused on the field of genetics and genomics in Iran in recent years and some efforts have been enforced and implemented. However, they are totally not adequate, considering the advances in medical genetics and genomics in the past two decades around the world. Overall, considering the lack of medical genetics residency programs in the Iranian health education system, big demand due to high consanguinity and intraethnic marriages, there is a lag in genetic services and necessity to an immediate response to fill this big gap in Iran. As clarified in the National constitution fundamental law and re-emphasized in the 6th National Development Plan, the Iranian government authority is in charge of providing the standard level of health including genetic services to all Iranian individuals who are in need.

Myositis Mimics—a Clinical Approach to a Diagnostic Challenge

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of disorders generally referred to as myositis. Myositis mimics are common and their overlapping features with IIMs can pose a diagnostic challenge. This review highlights the current knowledge of various myositis mimics, analyzes key distinguishing features from IIMs, and summarizes practical tips in assessing a patient with possible myositis. A new classification criteria for IIMs has been proposed by the European League against Rheumatism/American College of Rheumatology in 2017. Advances in medical genetics have expanded the spectrum of hereditary myopathies, and effective treatment has become available for some. Magnetic resonance imaging (MRI), although not without limitations, is more widely used to differentiate myositis mimics from IIMs. In the end, one must consider the clinical gestalt in formulating a diagnosis. A good clinical history, examination, and judicious use and interpretation of ancillary tests are key in approaching a patient with possible IIMs. Monitoring treatment response is also paramount, not only as a clue to reconsidering the diagnosis but also to prevent unwanted side effects and symptom exacerbation from steroids.

Differences in attitudes toward genetic testing among the public, patients, and health-care professionals in Korea

With further advances in medical genetics, genetic tests to determine predisposition to disease are becoming viable for a growing number of diseases. Accordingly, it has also become important to identify various viewpoints on genetic testing. The aims of this study were to examine awareness of and attitudes toward genetic testing among the general public (public), cancer patients (patients), and health-care professionals (clinicians and researchers) in Korea. The present survey was conducted from November 2016 to February 2017. The public and patients were surveyed via face-to-face interviews conducted by trained interviewers. Health-care professionals were surveyed via self-administered questionnaires. In total, 1500 individuals from the general public, 1500 cancer patients, 113 clinicians, and 413 researchers were surveyed. Most respondents from the public and patients had previously heard about genetic testing (public, 89.4%; patients, 92.7%, p < 0.01). Differences in attitudes toward genetic testing among the public, patients, and professionals were noted, although most respondents in the present study were aware of genetic testing. Most of the cancer patients tended to overestimate the potential benefit of genetic testing, whereas clinicians expressed concerns for genetic testing. Providing correct information to people who are scheduled to undergo or order genetic testing could help in making an informed decision thereon.

Medical genetic services in a developing country: lesson from Thailand.

The aim of the review was to give an example of how advances in medical genetics impact a developing country and how Thailand struggles to improve medical genetic services. Thailand is an example of a developing country with limited resources and low geneticist-to-population ratio. The country formally followed decentralized healthcare system (even though practically centralized) and is a nation with growing public interest in medical genetic technology. Nonetheless, efforts have been and are still being made in expanding clinical genetics services, improving access to laboratory diagnosis, increasing rare disease medication in national formulary, and the training of medical genetics personnel. For an endemic genetic disorder such as thalassemia, a universal prevention and control program is available and has had some success. Lesson learned in country like Thailand may be a useful model for other developing nations. Several strategies can be attempted to integrate the advances in medical genetics into medical practices in developing countries with relatively low income per capita and geographic discrepancy in healthcare distribution.

Genomics, Transcriptomics, and Epigenomics in Traumatic Brain Injury Research

The long-term effects and significant impact of the full spectrum of traumatic brain injury (TBI) has received increased attention in recent years. Despite increased research efforts, there has been little movement toward improving outcomes for the survivors of TBI. TBI is a heterogeneous condition with a complex biological response, and significant variability in human recovery contributes to the difficulty in identifying therapeutics that improve outcomes. Personalized medicine, identifying the best course of treatment for a given individual based on individual characteristics, has great potential to improve recovery for TBI survivors. The advances in medical genetics and genomics over the past 20 years have increased our understanding of many biological processes. A substantial amount of research has focused on the genomic, transcriptomic, and epigenomic profiles in many health and disease states, including recovery from TBI. The focus of this review chapter is to describe the current state of the science in genomic, transcriptomic, and epigenomic research in the TBI population. There have been some advancements toward understanding the genomic, transcriptomic, and epigenomic processes in humans, but much of this work remains at the preclinical stage. This current evidence does improve our understanding of TBI recovery, but also serves as an excellent platform upon which to build further study toward improved outcomes for this population.

Genetic Counselling: A Review and Update

The increasing availability of genetic tests confers to the speciality of genetic counselling a fast growing place in medical practice. Genetic counselling provides the link between genetic technologies and patient care. It is a communication process which deals with the human problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family. Recent dramatic advances in medical genetics have resulted in a comparable increase of interest in genetic counselling. These advances have included rapid growth in knowledge of the ways in which a large number of diseases are inherited, improvements in the ability to examine human chromosomes and detect chromosomal abnormalities, the ability to diagnose certain diseases in the second trimester of pregnancy, and the advent of screening programs for certain diseases in high risk populations.

Congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is a multifaceted disease and continues to be the most common cause of persistent hypoglycemia in infants. The purpose of the review is to highlight important recent developments regarding CHI. Several recent studies have highlighted the advances in medical genetics, imaging techniques, histological variety, and surgical decision making regarding CHI. The advancements have resulted in the ability to often distinguish between diffuse and focal disease, thus allowing a more focused medical and surgical approach to the patient. When genetic information is combined with advanced imaging and intraoperative histological analysis, surgical results have improved. Despite medical and surgical advancements, recent studies also reveal the need for better medical options for patients and that aggressive surgery may lead to the onset of diabetes. Current advances have improved the overall care of the patient with CHI, although there are still improvements to be achieved. The ability to apply these advancements is best accomplished with an experienced team consisting of geneticists, radiologists, endocrinologists, pathologists, and surgeons. Utilizing a team approach results in a complete evaluation and allows a customized care plan for each patient.

Trend of medicine of the 21st century

Until today, traditional clinical diagnosis and disease management was focused on the individual patient’s clinical symptoms and signs, medical and family history, data from laboratory and imaging evaluation that led to diagnose and treatment of illnesses. This is often a reactive approach to treatment, i.e., treatment starts after the symptoms and signs appear. Advances in medical genetics have enabled a more detailed understanding of the impact of genetics in diseases. It was the main reason for developing a so called personalized medicine. Large collaborative research projects (for example, the Human genome project) have laid the groundwork for the understanding of the roles of genes in human development and physiology. Even that revealed single nucleotide polymorphisms that pointed to some of the genetic variabilities between individuals. Important biological functions: growth, death, cellular movement and localization, differentiation, etc. are controlled by a process called signal transduction. This process is nearly entirely epi-genetic and governed by protein enzyme activity. Diseases such as cancer, based on genomic mutations, are functionally manifest as dysfunctional protein signal transduction. Historically, the pharmaceutical industry has developed medications based on empiric observations and more recently, on known disease mechanisms. For example, medications for diabetes aim to improve insulin release from the pancreas and the sensitivity of the muscle cells and fat tissues on the effect of insulin. Drugs for high cholesterol, affect the absorption, metabolism, and generation of cholesterol. It means that medications are developed based on mechanisms of disease that have been extensively studied over the past century. We hope that recent advancements in the genetic etiologies of common diseases will improve pharmaceutical development. Today we discovered that information about a patient’s proteomic, genetic and metabolic profile could be used to tailor medical care to that individual’s needs. One idea of this medical model is the development of diagnostics, whereby molecular assays that measure levels of proteins, genes or specific mutations are used to provide a specific therapy for an individual’s condition by stratifying disease status, selecting the proper medication and tailoring dosages to that patient’s specific needs. Besides that, many scientists and practitioners estimate that such methods might be used to assess a patient’s risk factor for a number of conditions and tailor individual preventative treatments such as nutritional immunology approaches. Contemporary potential applications of personalized medicine include pharmacogenetics, pharmacometabolomics and cancer management. Examples of pharmacogenetics include: Genotyping for single nucleotide polymorphisms in genes involved in the action and metabolism of warfarin. This medication is used clinically as an anticoagulant but requires periodic monitoring and is associated with adverse side effects. Recently, genetic variants in the gene encoding Cytochrome P450 enzyme CYP2C9, which metabolizes warfarin&nbsp;1, and the Vitamin K epoxide reductase gene&nbsp;(VKORC1), a target of coumarins2, have led to commercially-available testing that enables more accurate dosing based on algorithms that take into account the age, gender, weight, and genotype of an individual. Examples of personalized cancer management include: Testing for disease-causing mutations in the&nbsp;BRCA1&nbsp;and&nbsp;BRCA2genes, which are implicated in familial breast and ovarian cancer syndromes. Discovery of a disease-causing mutation in a family can inform “at-risk” individuals as to whether they are at higher risk for cancer and may prompt individualized prophylactic therapy including mastectomy and removal of the ovaries. More detailed molecular stratification of breast tumors may pave the way for future tailored treatments3. Targeted therapy is used for medications’ designing which targets epidermal grow factor receptors (EGFR) in a subset of patients with Non-Small Cell Lung Cancer (NSCLC). For example, Tyrosine kinase inhibitors such as erlotinib and gefitinib have been developed to treat NSCLC, where the mutation of the epidermal growth factor receptor gene (exon 19 - 21) in lung cancer cells was detected. These medications specifically inhibit the intracellular domain of this receptor, this way making blockade of intracellular signal transduction cascade which is responsible for cellular proliferation, invasion, metastasis, angiogenesis and inhibition of apoptosis. In the future, tissue-derived molecular information might be combined with an individual’s personal medical history, family history, data from imaging, and other laboratory tests to develop more effective treatments for a wider variety of conditions.

The Overlap between Headache and Epilepsy in the Light of Recent Advances in Medical Genetics

Migraineurs show an higher frequency of epilepsy (range 1–17%) than general population (0.5–1%), and at the same time migraine prevalence among patients affected by epilepsy is also higher (range 8–15%) than that reported in healthy individuals [11-13]. Especially in children this comorbidity is found often [14]. Seizures and migraine attacks share different pathophysiological mechanisms. Both events may be sign of an underlying brain lesion, or have a probably genetic origin. In this respect, it has been shown that in epilepsy occurs hyperexcitation, while in migraine a brief hyperexcitation period (depolarization) is followed by a long hypoexcitation period (spreading depression), followed again by hyperexcitation, as rebound phenomenon. Moreover, it has been shown that a disexcitability (hyper- and hypo-excitation in the same migraineurs at different points in time) underlines both the phenomenon [1]. Cortical Spreading Depression (CSD) is believed to underlie both migraine and epilepsy [15,16], even in patients affected by migraine without aura. CSD is characterized by a slowly propagating wave of sustained strong neuronal depolarization that generates transient intense spike activity as it progresses into the brain tissue, followed by neural suppression which may last for minutes. The phase of depolarization is associated with a regional cerebral blood flow increase, whereas the phase of reduced neural activity is associated with a reduction in blood flow [17]. It is crucial to remark that while an epileptic discharge can birth exclusively in the cortex, the pathophysiology of headache has its origin at multiple cortico-subcortical levels. Thus, the two cascades of events (headache and epilepsy) show independent ways that can crossover only at the cortical level [18,19]. In headache and epilepsy overlap, after the cortical cascade of events, their onset and propagation are triggered when CSD and epileptic focus reach a definite threshold, lower for CSD than for seizure [6,8,20,21]. Moreover, the onset of CSD and that of the epileptic seizure may facilitate each other [22]. Triggering factors may be environmental or individual (genetically determined or not), determining an ions flow and leading to CSD, through neuronal and glial cytoplasmic bridges rather than through

Survey report of gamete donors' and recipients' preferences regarding disclosure of third party reproduction outcomes and genetic risk information

Issues surrounding egg donation informed consent have recently been spotlighted due to advances in medical genetics. We sought information on attitudes and desires of donors and recipients to craft a program policy on counseling, disclosures, and re-contacting participants. Between April 2003 and September 2006 we conducted a questionnaire-based evaluation in our oocyte donor program. Donors pre-donation (n=265) and those undergoing the process (n=60), and recipients either ante- or postpartum (n=57), were asked about their desire to know/disclose obstetric outcomes (Question 1); willingness for contact in the event of a medical emergency (Question 2); and wish to know/disclose a liveborn's medical condition (Question 3). Pre-donation questioning among all donors generally revealed reticence to Question 1 (31% [n=83]), but were overall amenable with Questions 2 and 3 (83% [n=220] and 83% [n=219]). Following the donation process, no differences in Questions 1 and 2 were noted, but fewer donors were amenable with Question 3 (pre-donation 93% [n=56] versus post-donation 38% [n=23]; P<0.01). Overall, recipients were amenable to all three questions (88% [n=50], 74% [n=42] and 88% [n=50]), with similar responses both ante- and postpartum. All programs participating in gamete donation should establish a comprehensive disclosure policy, including consents that are built upon effective lines of communication between clinical staff and legal counsel assuring that parentage, relinquishment, and re-contact information in donor-recipient agreements are consistent with clinic consent documents and desires of both parties; All decisions must be adequately documented and honored and long-term counseling needs should be addressed.

Oregon Health &amp; Science University School of Medicine

Number of Activities: 145 Number of Hours of Instruction: 1,964 Number of Physician Participants: 29,136 Number of Other Learners: 17,094 Received Commercial Support: Yes Received Income from Advertising or Exhibits: Yes Participated in Joint Providership: Yes Offered Courses: Yes Offered Enduring Materials: Yes Offered Internet Enduring Materials: Yes Offered Performance Improvement: Yes Offered RSS: Yes Offered Test Item Writing: Yes

Developing a curriculum statement based on clinical practice: genetics in primary care.

Advances in medical genetics are increasingly being incorporated into clinical management outside specialist genetic services. This study was therefore undertaken to develop learning outcomes in genetics for general practice specialty training, using methods to ensure the knowledge, skills, and attitudes relevant to genetics in primary care were identified. To identify key knowledge, skills, and attitudes in genetics and to synthesise these into learning outcomes to assist training in genetics for primary care. Delphi survey and review by expert group. Primary care practices and Regional Genetics Centre in the West Midlands region of the UK. A modified Delphi survey involved GP trainers, programme directors, and geneticists (n = 60). The results, along with results from a survey of GP registrars, were reviewed by an expert group, which included GPs, geneticists, and educationalists. Core genetics topics for GPs were identified, prioritised, and developed into competency statements in the style of the curriculum structure of the Royal College of General Practitioners. The development of the GP curriculum statement Genetics in Primary Care was based on a study of educational needs, incorporating the views of practitioners (GP trainers, programme directors, and registrars) and specialists (clinical geneticists). This inclusive approach has enabled the identification of learning outcomes which directly reflect clinical practice.

The development of core learning outcomes relevant to clinical practice: identifying priority areas for genetics education for non-genetics specialist registrars

Advances in medical genetics are increasingly impacting on clinical practice outside specialist genetic services. It is widely acknowledged that physicians will need to use genetics knowledge and skills in order to incorporate these advances into patient care. In order to determine priority areas for genetics education for non-genetics specialist registrars, an educational needs assessment was undertaken. Consultants from cardiology, dermatology, neurology and genetics identified genetics knowledge, skills and attitudes required by non-genetics specialty trainees. From these, and informed by trainees' views of genetic education, six genetics learning outcomes that non-genetics medical specialty trainees should attain by the end of their training have been identified, each linked to core knowledge, skills and attitudes. These core concepts can be taught with reference to specialty-specific conditions to highlight their relevance to clinical practice. The results of this study are informing the genetic component of postgraduate medical training curricula.

Patient preferences regarding recontact by cancer genetics clinicians

Ongoing advances in cancer genetics lead to new opportunities for early disease detection, predictive genetic testing and potential interventions. Limited information exists on patient preferences concerning recontact to provide updated information. We evaluated colon cancer genetics patient preferences concerning recontact about advances in medical genetics. Information was mailed to 851 individuals seen at the Colon Cancer Risk Assessment Clinic at the Johns Hopkins Hospital and to participants in a colon cancer gene testing study seen during an 8-year period. Information provided included description of advances in gene testing technology, discovery of MSH6 and MYH genes, detailed fact sheets and a survey of patient preferences for notification and potential uses of new information. Most patients wanted an ongoing relationship with genetics providers (63%), reinitiated by genetics providers (65%) and contact only with information specifically relevant to them (51%). Most preferred personalized letters as the means of contact (55%). Reasons for and against recontact and circumstances in which individuals would pursue additional genetic testing were also tabulated. There were few statistically significant differences in the responses between clinic and study participants. Patients evaluated in a colon cancer risk assessment clinic want updated information at a rate similar to those who participated in a colon cancer gene testing study. These findings have implications for the consultative nonlongitudinal nature of such clinics and suggest patient preferences for personally-tailored information could be labor intensive.

The Role of Aldosterone in Renal Sodium Transport

Aldosterone is the body's major hormone involved in volume homeostasis because of its effects on sodium reabsorption in the distal nephron. Our comprehension of the signaling pathways that this mineralocorticoid unleashes has been enhanced through the convergence of bedside physiologic observations with advances in medical genetics and molecular biology. This overview updates our current understanding of the aldosterone-initiated pathways throughout the distal nephron to promote sodium retention. Three essential features of the pathways are explored: how the mineralocorticoid gains specificity and targets gene transcription in distal tubular cells; how the key endpoints of aldosterone action in these cells-the epithelial sodium channel, the thiazide-sensitive sodium chloride cotransporter, and Na,K,ATPase-are regulated; and how 3 kinases, directly or indirectly, are activated by aldosterone and serve as critical intermediaries in regulating the sodium transporters. Remarkably, perturbations in many genes integral to aldosterone-induced pathways result in blood-pressure abnormalities. The familial disorders of hypertension and hypotension that follow from these mutated genes are presented with their molecular and physiologic consequences. The clustering of so many genetic disorders within the aldosterone-sensitive distal nephron supports the hypothesis that renal sodium regulation plays a pivotal role in long-term blood-pressure control. Identifying and characterizing other components of the pathways that modulate these sodium transporters represent the core challenges in this scientific field. It is posited that meeting these challenges will help elucidate the pathogenesis of human hypertension and provide new therapeutic options for its treatment.

Introductory Speech for Joan Marks

Introductory Speech for Joan Marks

Genetic approaches to unraveling reproductive disorders: examples of bedside to bench research in the genomic era.

Despite the rapid advances in medical genetics, many clinicians and investigators remain unaware of the general approaches that can be used to map genes. Although there are specific challenges to using genetic approaches in reproductive medicine, the following report summarizes mapping efforts for three diseases: adrenal hypoplasia congenita, hypergonadotropic ovarian failure, and polycystic ovary syndrome. The themes of rare and novel phenotypes, genetically homogenous populations, and genotype/phenotype correlations are emphasized.