Recent Advances In Genetic Research Research Articles

Novel Pathogenic Variants in Hereditary Cancer Syndromes in a Highly Heterogeneous Cohort of Patients: Insights from Multigene Analysis.

Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.

Genetic mutations in pyoderma gangrenosum, hidradenitis suppurativa, and associated autoinflammatory syndromes: Insights into pathogenic mechanisms and shared pathways.

Pyoderma gangrenosum (PG), hidradenitis suppurativa (HS), and the associated autoinflammatory syndromes, including pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome, and pyogenic arthritis, pyoderma gangrenosum, acne, and suppurative hidradenitis (PAPASH) syndrome are dermatological conditions characterized by chronic inflammation and tissue damage. Recent advances in genetic research have identified specific mutations associated with these disorders, shedding light on their underlying pathogenic mechanisms. This review aims to summarize the current knowledge of identified mutations and presumed pathophysiology in PG, HS, and the associated autoinflammatory syndromes.

Evidence of Autoimmune Involvement in the Pathogenesis of Charcot Neuroarthropathy: A Novel Hypothesis with Preliminary Data.

Charcot neuroarthropathy is a devastating condition that places patients at risk for poor outcomes. Although the condition was first described in 1703, knowledge of the causative agent(s) has yet to be fully understood. Recent advances in genetic research have helped to identify potential mechanisms and pathways for the enigmatic destruction and deformities that are often associated with the condition; however, alternative pathways have been proposed. For the purpose of this discussion, we will discuss the human leukocyte antigen, which is one of the most researched contributors to autoimmune pathology and, more recently, has been linked to diabetic complications.

Hereditary dystrophies of the posterior segment of the retina

Hereditary dystrophies of the posterior segment are the common name for a group of syndromic diseases in which the retina is affected. Until recently, the information available on these diseases has been limited and a wide range of clinical findings were reported. However, recent advances in genetics research suggest a better outlook. Here we review the recent advances in the following: Pseudoxanthoma Elasticum, Refsum Disease, Bietti Cryistalline Dystrophy, Alport’s Syndrome

Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy

Epilepsy represents one of the most common neurological disorders, affecting an estimated 50 million people worldwide. Recent advances in genetic research have uncovered a large spectrum of genes implicated in various forms of epilepsy, highlighting the heterogeneous nature of this disorder. Appropriate animal models are essential for investigating the pathological mechanisms triggered by genetic mutations implicated in epilepsy and for developing specialized, targeted therapies. In recent years, zebrafish has emerged as a valuable vertebrate organism for modeling epilepsies, with the use of both genetic manipulation and exposure to known epileptogenic drugs, such as pentylenetetrazole (PTZ), to identify novel anti-epileptic therapeutics. Deleterious mutations in the mTOR regulator DEPDC5 have been associated with various forms of focal epilepsies and knock-down of the zebrafish orthologue causes hyperactivity associated with spontaneous seizure-like episodes, as well as enhanced electrographic activity and characteristic turn wheel swimming. Here, we described the method involved in generating the DEPDC5 loss-of-function model and illustrate the protocol for assessing motor activity at 28 and 48 h post fertilization (hpf), as well as a method for recording field activity in the zebrafish optic tectum. An illustration of the effect of the epileptogenic drug PTZ on neuronal activity over time is also provided.

Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy.

Epilepsy represents one of the most common neurological disorders, affecting an estimated 50 million people worldwide. Recent advances in genetic research have uncovered a large spectrum of genes implicated in various forms of epilepsy, highlighting the heterogeneous nature of this disorder. Appropriate animal models are essential for investigating the pathological mechanisms triggered by genetic mutations implicated in epilepsy and for developing specialized, targeted therapies. In recent years, zebrafish has emerged as a valuable vertebrate organism for modeling epilepsies, with the use of both genetic manipulation and exposure to known epileptogenic drugs, such as pentylenetetrazole (PTZ), to identify novel anti-epileptic therapeutics. Deleterious mutations in the mTOR regulator DEPDC5 have been associated with various forms of focal epilepsies and knock-down of the zebrafish orthologue causes hyperactivity associated with spontaneous seizure-like episodes, as well as enhanced electrographic activity and characteristic turn wheel swimming. Here, we described the method involved in generating the DEPDC5 loss-of-function model and illustrate the protocol for assessing motor activity at 28 and 48 h post fertilization (hpf), as well as a method for recording field activity in the zebrafish optic tectum. An illustration of the effect of the epileptogenic drug PTZ on neuronal activity over time is also provided.

Bioinformatic Exploration for Prognostic Significance of Sphingolipid Metabolism-Related Genes in Invasive Ductal Carcinoma Using the Cancer Genome Atlas Cohort.

IntroductionSphingolipid metabolism is a highly controlled process that is involved in regulating bioactive lipid signaling pathways and serves important roles in several cellular processes in breast cancer. Invasive ductal carcinoma (IDC), which is characterized by the malignant proliferation of the ductal epithelium and stromal invasion, is the most common type of breast cancer. Recent advances in genetic research have accelerated the discovery of novel prognostic factors and therapeutic targets for the disease. The aim of the present study was to investigate the expression and prognostic significance of sphingolipid metabolism-related genes in female IDC.MethodsThe present study used gene expression RNAseq data obtained from The Cancer Genome Atlas breast invasive carcinoma (TCGA BRCA) datasets.ResultsSphingolipid metabolism-related genes exhibited dysregulated mRNA expression levels in IDC. The Student’s t-test revealed that SMPDL3B, B4GALNT1, LPAR2, and LASS2 were significantly upregulated, while LASS3, LPAR1, B4GALT6, GAL3ST1, HPGD, ST8SIA1, UGT8, and S1PR1 were significantly downregulated in female IDC tissues compared with normal solid tissues. Kaplan–Meier survival analyses revealed that high SMPDL3B mRNA expression levels were associated with good prognosis in female IDC, suggesting that SMPDL3B plays a tumor suppressor role. To the best of our knowledge, the present study was the first to report that dysregulated expressions of SMPDL3B are significantly associated with age, estrogen receptor status, progesterone receptor status, and histological subtype.ConclusionTaken together, our study indicated that SMPDL3B may have a pathophysiological role and serve as a novel prognostic biomarker in IDC.

Reelin Alleviates Mesenchymal Stem Cell Senescence and Reduces Pathological α-Synuclein Expression in an In Vitro Model of Parkinson's Disease.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. The mechanisms underlying PD remain to be fully elucidated, and research into treatments for this condition is ongoing. Recent advances in genetic research have shed light on the mechanisms underlying PD. In this study, we used PD and control mesenchymal stem cells (MSCs) obtained from adipose tissues to confirm the differences between groups at the cellular and molecular levels. The results revealed that in PD MSCs, cell viability was clearly lower, and the rate of cell senescence was higher compared to the controls. Next, to compare the gene expression in PD and control cells, transcriptome analysis was performed. Genes in pathways, including extracellular matrix (ECM) receptor interaction, P53 signaling, and focal adhesion, were down-regulated in PD. Among genes related to ECM receptor interaction, RELN gene expression was markedly decreased in PD cells; however, after being treated with recombinant Reelin protein, a significant increase in cell viability and a decrease in α-Synuclein aggregation and cell senescence were observed. In conclusion, Reelin affects PD by positively influencing the cell characteristics. Our findings will facilitate research into new treatments for PD.

Retinopathies with Metabolic Disorders

Hereditary dystrophies of the posterior segment are the common name for a group of syndromic diseases in which the retina is affected. Until recently, the information available on these diseases has been limited and a wide range of clinical findings was reported. However, recent advances in genetics research suggest a better outlook. Here we review the recent advances in the following: Pseudoxanthoma Elasticum, Refsum Disease, Bietti Crystalline Dystrophy, Alport’s Syndrome

THE ZEBRAFISH ANIMAL MODEL (Danio rerio) USED FOR DIFFERENT THERAPEUTIC APPROACHES FOR THE SUPPRESSION OF EPILEPTIC CRISIS: A SYSTEMATIC REVIEW

A epilepsia representa uma das doenças neurológicas mais comuns, afetando cerca de 70 milhões de pessoas em todo o mundo. Avanços recentes na pesquisa genética descobriram um grande espectro de genes implicados em várias formas de epilepsia, sua causa pode ser por inflamação, neurotrauma ou malformações cerebrais, destacando a natureza heterogênea desse distúrbio. Além disso, infelizmente, as drogas epiléticas mais antigas têm muitos efeitos colaterais, sendo o comprometimento cognitivo o principal efeito colateral que afeta a vida diária de pessoas com epilepsia. Modelos animais apropriados são essenciais para investigar os mecanismos patológicos desencadeados por mutações genéticas implicadas na epilepsia e para desenvolver terapias específicas e direcionadas. No entanto, os modelos de doenças do zebrafish (Danio rerio) são relevantes para a fisiopatologia das doenças humanas. Nos últimos anos, o zebrafish emergiu como um valioso organismo vertebrado para modelar epilepsias, com o uso de manipulação genética ou exposição a drogas epileptogênicas conhecidas, como o pentilenetetrazol (PTZ), para identificar novas terapêuticas antiepilépticas. O objetivo do presente estudo foi realizar uma revisão sistemática da literatura de modo a compreender de que forma zebrafish vem sendo utilizado para o estudo da epilepsia. Para tanto, foi feita uma pesquisa da literatura nas bases de dados Medline, Lilacs, Science, Citation Index, SciELO, PUBMED, Google Acadêmico, Periódicos CAPES e BVS Bireme. As palavras-chave utilizadas foram: ‘’Suppression of the epileptic crisis’’, ‘’Animal Model’’, ‘’Zebrafish’’ nas bases de dados. Como resultados, foi possível observar 16 artigos incluídos após a síntese qualitativa, destes, 44% dos artigos analisaram determinado fármaco no tratamento da epilepsia, 30% tratavam sobre a indução de epilepsia para estudo das vias envolvidas nesta doença, 22% realizou estudos estritamente envolvidos à Síndrome de Dravet. Em conclusão, pode-se afirmar desenvolver um modelo animal para distúrbios cerebrais, particularmente epilepsia, é muito difícil devido à complexidade da doença. A maior parte da pesquisa pré-clínica da epilepsia tem se concentrado em roedores. Porém, pesquisas recentes apontam o zebrafish como um excelente alvo de análises laboratoriais, pois possui uma grande semelhança com os mamíferos e é altamente vantajoso com suas propriedades únicas, como fertilização externa, tamanho pequeno, bem como clareza ótica dos embriões. O papel central dos receptores na epilepsia demonstra a utilidade potencial dos alvos para controlar as convulsões nesses modelos animais.

Unsettling disciplinary frontiers

Recent advances in genetic research provide anthropologists with an opportunity to reconsider the meaning and importance of interdisciplinary research. This piece suggests that interdisciplinary thinking can help to redevelop health policies aimed at improving access to new genetic technology and addressing many health care inequities. Drawing from research on access to genetic testing among women with a breast cancer diagnosis in the United States, I explore how patient perspectives can be used to redefine how policy makers interpret the utility of genetic medicine. Individuals undergoing genetic testing describe how genetic knowledge is translated into salient change in their lives, a view rarely recognized in conventional evaluations of genetic medicine. This work also recognizes how the ‘potentialities’ of genetic medicine both fuel the engine of ongoing genetic research and motivate individuals to imagine possible future actions to improve health. This reflection is meant to provoke debate and contribute to discussion about how health policies can be designed to improve inequities in access to genetic medicine.

Improving access to genetic testing for adults with intellectual disability: A literature review and lessons from a quality improvement project in East London.

Recent advances in genetic research have led to an increased focus on genetic causes of intellectual disability (ID) and have raised new questions about how and when clinicians offer genetic testing and the nature of communication around this decision with patients and carers. Determining the right approach to such discussions is complicated by complexities of communication, consent, and capacity and ethical concerns about genetic testing in this population. In this article, we briefly discuss the recent advances in genetic research relevant to people with intellectual disability, highlighting the challenges that might arise when undertaking genetic testing in this population. We then describe how we have used a Quality Improvement methodology to develop a clinical pathway for routine genetic testing for adults with intellectual disability in a clinical setting in East London.

Genetic testing, prevention and health care insurance markets

Since this special issue of medecine/sciences is devoted to personalized medicine, it seems unnecessary for two economists to summarize or discuss, from a medical perspective, recent advances in genetic research. We rather focus on the consequences of improved genetic testing on the health insurance market, on how this market may be affected and on the degree of coverage offered to consumers according to the regulations implemented. More precisely, we first study the value of the information conveyed by genetic tests and we then decompose this value into several components according to the regulations implemented in various health insurance markets.

The genetic basis of music ability.

Music is an integral part of the cultural heritage of all known human societies, with the capacity for music perception and production present in most people. Researchers generally agree that both genetic and environmental factors contribute to the broader realization of music ability, with the degree of music aptitude varying, not only from individual to individual, but across various components of music ability within the same individual. While environmental factors influencing music development and expertise have been well investigated in the psychological and music literature, the interrogation of possible genetic influences has not progressed at the same rate. Recent advances in genetic research offer fertile ground for exploring the genetic basis of music ability. This paper begins with a brief overview of behavioral and molecular genetic approaches commonly used in human genetic analyses, and then critically reviews the key findings of genetic investigations of the components of music ability. Some promising and converging findings have emerged, with several loci on chromosome 4 implicated in singing and music perception, and certain loci on chromosome 8q implicated in absolute pitch and music perception. The gene AVPR1A on chromosome 12q has also been implicated in music perception, music memory, and music listening, whereas SLC6A4 on chromosome 17q has been associated with music memory and choir participation. Replication of these results in alternate populations and with larger samples is warranted to confirm the findings. Through increased research efforts, a clearer picture of the genetic mechanisms underpinning music ability will hopefully emerge.

Recent Advances in the Understanding of Genetic Susceptibility to Chronic Pain and Somatic Symptoms

Regional (e.g., low back) and widespread chronic pain disorders are common in the general population and are known to be heritable. Recent research suggests that genetic factors increase the risk of developing chronic pain independent of the site of pain. Candidate gene studies have been conducted on key pathways to elucidate susceptibility genes that are likely to be involved in both the sensory and affective components of pain. Findings have been largely equivocal, predominantly due to small sample size, but larger studies of pain in general population samples are being conducted. Interesting candidate genes from animal models and monogenic pain disorders are beginning to emerge. Recent advances in genetics research have yet to make an impact in the pain field but provide considerable scope for future research efforts.

Recent advances in genetic research of inflammatory bowel disease

Recent advances in genetic research of inflammatory bowel disease

The use of buccal smears for a non-invasive screening of the 35delG mutation of the Connexin-26 gene in hearing impaired young children

Recent advances in genetic research indicate that about 50% of congenital deaf patients have a genetic background, with mutations in the Connexin-26 gene being the most frequent one. Screening methods for the genetic cause of deafness have so far mostly been based on the use of peripheral whole blood as DNA source. The use of buccal smears for the genetic screening of deaf patients presents an interesting alternative to drawing blood, especially in young children. In order to validate this method, we compared results from buccal smears from very young deaf children (age<or=3 years) and deaf patients older than 3 years with the results from blood samples deriving from the same patients. The detection of the 35delG mutation in the Connexin-26 gene was chosen to demonstrate the method's feasibility. Blood and buccal smears were collected for genetic analysis from 29 very young deaf children (Group 1: age<or=3 years) and 31 deaf patients older than 3 years (Group 2) during their clinical pre-evaluation for cochlear implantation. Genomic DNA was isolated from blood as well as from buccal smears. Yield of both sources was determined by photometric evaluation of the isolated DNA concentration. Genomic DNA isolated from blood and buccal smears was then submitted to PCR-mediated site-directed mutagenesis followed by BS1 YI restriction and electrophoresis. The results for 35delG detection in DNA originating from blood were compared to those of buccal smears. Quantitative DNA analysis showed that both sources provided adequate amounts of DNA for PCR. No significant difference was found between Group 1 and Group 2 considering either the DNA amount isolated from blood or from buccal smears. In all 60 patients, DNA isolated from blood revealed the same results concerning the presence of the 35delG mutation as DNA originating from buccal smears. This study demonstrates that buccal smears are an adequate, reliable source of genomic DNA providing material for genetic tests that can especially help to avoid drawing blood from very young children for the genetic screening of deafness.

Paget disease of bone

Purpose of review Paget disease of bone is a prevalent disorder of bone metabolism, described as the second most common bone disease to affect an aging population in the United States after osteoporosis. Although recent studies suggest a decrease in mortality rates in Great Britain between 1951 and 1970 and a decline in prevalence and severity from the 1970s to 1990s, Paget disease continues to affect an important segment of the population with progressive deformity of bone, pain, and impaired quality of life. This article reviews the theories of pathogenesis and examines some of the relevant epidemiologic data. The pivotal role of the osteoclast in mediating this disease is discussed, followed by a brief summary of the pathology, clinical features, the diagnostic approach to patients, and therapeutic experience with increasingly potent bisphosphonates. Recent findings The cause of the disorder remains elusive but may be a viral infection affecting osteoclasts in a genetically predisposed person. Recent advances in genetic research suggest that lesions affecting the signaling pathways of receptor for activation of nuclear factor-Kb (RANK) and its receptor are critical in the expression of familial and some sporadic Paget disease, but the environmental determinants and triggers remain controversial. Previous viral infections, pet ownership, and geographical differences are some of the features identified by epidemiologic studies that may play a causative role. Much progress is being made in characterizing pagetic osteoclasts further in terms of their altered structure and function and the likely role of cytokines and of the marrow microenvironment. Studies with nitrogen-containing bisphosphonates have demonstrated their efficacy in inducing clinical and skeletal improvement and biochemical remissions in most patients with Paget disease. Summary Although the cause of Paget disease remains enigmatic, progress continues in understanding of the pivotal role of the osteoclast in Paget disease, with an increasing number of factors now implicated in abnormal osteoclast structure and function. There have been major therapeutic advances with the availability of increasingly potent bisphosphonates with real potential for prevention of progressive changes and for long-lasting remissions in most patients with Paget disease.

Gene-based deafness research: ion transport and hearing.

The cochlea is a sensory organ that converts physical (sound) stimulation into electrical signals. This process is fundamentally and substantially based upon the ion transport system. Here, I summarize the physiological and molecular biological aspects of transporters, channels and receptors expressed in the cochlea. With reference to these findings, recent advances in genetic research on hereditary deafness are discussed.

The messenger's dilemmas - giving and getting information in genealogical mapping for hereditary cancer

Recent advances in genetic research can provide constructive preventive possibilities for individuals and society but also provide physicians and laypersons with new problems. For instance, in consultations dealing with the risk of getting hereditary cancer, physicians have to balance between the role of clinician, attending to the needs of a certain individual, and the role of researcher, collecting vital data for important research. Individuals taking part in these consultations not only have to interpret the information provided by the physicians. They might also be faced with the problem of informing others, often close kin, in a similar risk situation, or on the physician's behalf obtain information from them. They do not only receive bad news about themselves but are placed in a messenger's dilemma. The study is based on discourse data from 31 audio-taped talks between a physician and a person seeking information. Analyses of the consultations reveal how individuals seeking information about possible future diseases find themselves in a position where not only informing unknowing relatives, but also obtaining information from them, is experienced as giving them bad news.