Genetic Profile Research Articles

From genes to populations: developing precision medicine for acral lentiginous melanoma through in silico and epidemiological studies

Acral Lentiginous Melanoma (ALM) is a rare and aggressive form of melanoma that predominantly affects individuals with darker skin tones, posing significant challenges in both diagnosis and treatment. The growing demand for more personalized and effective treatments has led to the exploration of innovative approaches to tackle these challenges. This study integrates in silico drug design with comprehensive statistical analysis to identify and validate therapeutic targets specific to ALM. Key genes such as PLD1, CDKN2A, KIT, TERT, and NRAS were identified using advanced bioinformatics tools like DisGeNET, PANTHER DB, Network Analyst, and STRING DB. In parallel, a detailed demographic analysis involving 248 patients was conducted using SPSS, shedding light on factors influencing knowledge and awareness of ALM within affected populations. The findings from this dual approach emphasize the critical need for tailored therapeutic strategies that account for both genetic factors and patient demographics. The projected increase in ALM cases and the associated need for targeted therapies underscore the importance of continuing research into specialized treatments that can address the unique characteristics of this melanoma subtype. By advancing our understanding of ALM’s genetic profile and epidemiology, this study lays the foundation for the development of precision medicine solutions that could significantly improve patient outcomes and overall management of this aggressive disease.

Metachronous Bilateral Adrenal Neuroblastoma: A Case Report and Literature Review.

A baby presented with a large right adrenal mass, multiple hepatic lesions and diffuse bone marrow infiltration when she was just over 1 month old. After needle biopsy and a histologic definition of neuroblastoma, she underwent chemotherapy and a subsequent complete resection. Three years after diagnosis, a large left adrenal localized mass was detected. The patient underwent complete surgical excision, and a diagnosis of poorly differentiated neuroblastoma with multiple lymph nodes involvement was defined. Adjuvant chemotherapy was initiated. To our knowledge, it is the first case report of metachronous bilateral adrenal neuroblastomas harboring completely different genetic expression profiles.

Impact of Human Immunological Responses and Viral Genetic Diversity on Outbreak of Human Monkeypox Virus. A Comprehensive Literature Review Study

Monkeypox was caused by Monkeypox Virus (MPXV) and can infect both humans and animals. An understanding of the interplay between host immunity and genetic diversity was necessary to understand the etiology and epidemiology of monkeypox disease. Objective: To clarify how genetic differences and host immune responses interact when a moneypox infection occurs. Furthermore, we also aim to provide insights into individual variability in illness outcomes and possible treatment targets by investigating how distinct genetic profiles affect immune system activation and efficacy. Methods: Recent research on monkeypox, concentrating on the immune response mechanisms of the host and genetic variables linked to virus vulnerability have thoroughly analyzed. For this purpose, the data were searched from various research engines such as google scholar, pubmed, medline etc., by using different key words i.e., monkeypox and host immunity, monkeypox and antibodies interactions, monkeypox outbreak, mnkeypox strains. Conclusions: The way a monkeypox infection progresses and turns out was greatly influenced by the interplay between host genetic differences and immunological responses. Public health initiatives and the creation of tailored treatment plans can both benefit from the identification of genetic markers linked to immunological response profiles and vulnerability.

Coronary Artery Disease, Family History, and Screening Perspectives: An Up-to-Date Review.

Family history for CAD (coronary artery disease) is an established cardiovascular (CV) risk factor and it is progressively acquiring importance in patients' CV risk stratification. Numerous studies have demonstrated that individuals with a first-degree relative affected by CAD have a significantly higher risk of developing the condition themselves; in particular, when CAD occurs at an early age in relatives. Indeed, recently published CCS (chronic coronary syndrome) ESC (European Society of Cardiology) guidelines include family history (FH) as a risk factor to consider when calculating pre-test risk for CAD. ESC guidelines on preventive cardiology (2021) only suggested CV risk assessment in the presence of a positive FH for CV disease, not considering it in the actual risk scores. Evidence suggests that positive anamnesis for relatives affected by CAD correlates with ACS (acute coronary syndrome) and CAD, with slight differences in relative risk as far as the degree of kinship is concerned. Genetic factors contribute to this correlation by influencing key processes that affect heart health, such as cholesterol metabolism, blood pressure regulation, and inflammatory responses. New technologies in the genetics field are increasing the availability of genome sequencing, and new polymorphism panels are being tested as predictive for CAD, objectifying familiarity. Advances in imaging techniques allow the assessment of coronary atherosclerosis and its composition, and these are acquiring strength in evidence and recommendations in ESC guidelines as a way to define coronary disease in low and low-to-intermediate risk patients and to guide medical therapy and interventional procedures. Use of these emerging tools to guide screening is likely to be extended, beyond high CV risk patients, to individuals with FH for early CAD and/or specific genetic profiles, as recent evidence in the literature is suggesting.

Pharmacogenetic Panel Testing: A Review of Current Practice and Potential for Clinical Implementation.

Pharmacogenetics (PGx) aims to optimize drug treatment outcomes by using a patient's genetic profile for individualized drug and dose selection. Currently, reactive and pretherapeutic single-gene PGx tests are increasingly applied in clinical practice in several countries and institutions. With over 95% of the population carrying at least one actionable PGx variant, and with drugs impacted by these genetic variants being in common use, pretherapeutic or preemptive PGx panel testing appears to be an attractive option for better-informed drug prescribing. Here, we discuss the current state of PGx panel testing and explore the potential for clinical implementation. We conclude that available evidence supports the implementation of pretherapeutic PGx panel testing for drugs covered in the PGx guidelines, yet identification of specific patient populations that benefit most and cost-effectiveness data are necessary to support large-scale implementation.

Exploring the Genetic Diversity of Mycoplasma hyopneumoniae in Pigs with Pneumonia and Pleurisy at Slaughter.

Mycoplasma (M.) hyopneumoniae is the key pathogen of the porcine respiratory disease complex (PRDC) and contributes to pleurisy in pigs. Due to its limited metabolism and laborious cultivation, molecular tools are useful for diagnosis. This study investigated the genetic diversity of M. hyopneumoniae in slaughter pigs with pneumonia and pleurisy, and it assessed co-infections by Pasteurella multocida type A (PM), Actinobacillus pleuropneumoniae (APP), and swine influenza virus A (sIVA). Lungs (n = 70) with different pleurisy scores and lesions compatible with M. hyopneumoniae infection were collected for convenience. Macroscopic and microscopic evaluations were performed. M. hyopneumoniae was detected using qPCR, and MLST was used for genetic characterization. Co-infections with PM and APP were also evaluated by qPCR, while the immunohistochemistry assessed sIVA infection. All lungs were positive for M. hyopneumoniae. Histopathology confirmed M. hyopneumoniae-associated lesions. MLST characterization was possible in 25 lungs and revealed 10 distinct allelic profiles, with none matching known sequence types in the public database. Co-infections were detected in 40% of the samples with APP and 32% with PM, with 12% showing both pathogens and 52% of the samples presenting microscopic lesions compatible with sIVA infection. The diverse genetic profiles found underscore the need for research on isolation and potential pathogenic variations.

TMPRSS2:ERG Gene Fusion Might Predict Resistance to PARP Inhibitors in Metastatic Castration-resistant Prostate Cancer.

The emergence of novel DNA damage repair (DDR) pathways in molecular-target therapy drugs (MTTD) has shown promising outcomes in treating patients with metastatic castration-resistant prostate cancer (mCRPC). About 25% of mCRPC patients have actionable deleterious aberrations in DDR genes, primarily in the homologous recombination (HR) pathway. However, the response rate in patients with BRCA1/2 or mutations in HRR-related genes is only 45%-55%, when exposed to poly ADP ribose polymerase (PARP) inhibitor-based therapy (PARPi). A frequent characteristic feature of prostate cancer (PC) is the occurrence of genomic rearrangement that affects the transmembrane protease serine 2 (TMPRSS2) and E26 transformation-specific (ETS)- transcription factor-related gene (ERG). In this study, a total of 114 patients with mCRPC had their RNA and DNA sequenced using next-generation sequencing. Based on their genetic profile of deleterious gene alterations of BRCA1/2 or ATM, six patients were selected for PARPi. Patients with TMPRSS2:ERG gene fusion and homozygous alteration in ATM or BRCA2 (n=2) or heterozygous alterations (BRCA1 or BRCA2) and lack of TMPRSS2:ERG gene fusion (n=2) did not show clinical benefit from PARPi (treatment duration <16 weeks). In contrast, patients (n=2) without TMPRSS2:ERG gene fusion and homozygous deleterious alterations in ATM or BRCA2 all had clinical benefit from PARPi (treatment duration ≥16 weeks). The TMPRSS2:ERG transcript product might be used as a PARPi resistance biomarker.

Unusual familial cystic kidney disease: combining fine radiologic and genetic evaluation to solve the case

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease, characterized by enlarged kidneys with numerous cysts, high blood pressure, and a variety of extrarenal complications. This disease is a significant cause of renal failure and requires accurate differentiation from other cystic kidney diseases, especially when family history does not clearly indicate ADPKD. This is crucial due to differences in prognosis, treatment, and familial implications. Advanced molecular genetics and imaging techniques are employed to diagnose and assess the prognosis of patients and their families.Case presentationThe case study revolves around three patients from the same family—two sisters and one daughter—referred to a nephrology department for ADPKD management. The initial proband, a 42-year-old woman, experienced abdominal discomfort leading to an ultrasound that suggested ADPKD. However, MRI findings indicated standard-sized kidneys with bilateral parapelvic cysts, and no genetic markers for ADPKD were found. Her sister, presenting with controlled hypertension and similar ultrasound findings, also had her initial ADPKD diagnosis refuted by MRI and genetic testing, which revealed no significant mutations. The daughter, however, exhibited a different scenario with enlarged kidneys and multiple cysts characteristic of early-stage ADPKD. Genetic testing confirmed a deleterious PKD1 mutation, suggesting a de novo mutation, as her father showed no signs of the disease.ConclusionThis study highlights the complexity and necessity of thorough diagnostic processes in suspected ADPKD cases to prevent misdiagnosis. The initial symptoms and imaging might misleadingly suggest ADPKD, as seen in the cases of the two older patients. Still, further detailed imaging and genetic analyses revealed no ADPKD, preventing inappropriate treatment and stress. In contrast, the younger patient's distinctive clinical and genetic profile confirmed ADPKD, illustrating the variability within even closely related individuals. Such detailed assessments are crucial in guiding correct treatment decisions and providing accurate familial counseling, emphasizing the importance of considering a broader spectrum of renal cystic disorders before confirming a diagnosis of ADPKD.

Navigating the omics landscape in precision medicine: A bidirectional approach to patient care

This paper presents a novel bidirectional approach to precision medicine that combines proteomic, peptidomic and metabolomic analyzes with clinical data and genome-wide association studies (GWAS). This innovative strategy improves patient care by enabling a dynamic exchange from “patient to molecular pathway” and back, which significantly refines patient cohort stratification, improves diagnostic accuracy and personalizes treatment strategies. At the heart of this approach is the use of comprehensive multi-omics data to improve patient management by tailoring interventions to individual molecular profiles. This two-way flow not only optimizes treatment based on real-time insights from molecular pathways, but also improves the application of GWAS results in clinical scenarios. Advanced computational tools such as machine learning and network analysis are critical for navigating these complex data sets and translating intricate molecular data into actionable treatment plans. This integrated, adaptive framework promises to reshape the future of healthcare by tailoring treatments to patients' unique biological and genetic profiles.

CPMKG: a condition-based knowledge graph for precision medicine.

Personalized medicine tailors treatments and dosages based on a patient's unique characteristics, particularly its genetic profile. Over the decades, stratified research and clinical trials have uncovered crucial drug-related information-such as dosage, effectiveness, and side effects-affecting specific individuals with particular genetic backgrounds. This genetic-specific knowledge, characterized by complex multirelationships and conditions, cannot be adequately represented or stored in conventional knowledge systems. To address these challenges, we developed CPMKG, a condition-based platform that enables comprehensive knowledge representation. Through information extraction and meticulous curation, we compiled 307 614 knowledge entries, encompassing thousands of drugs, diseases, phenotypes (complications/side effects), genes, and genomic variations across four key categories: drug side effects, drug sensitivity, drug mechanisms, and drug indications. CPMKG facilitates drug-centric exploration and enables condition-based multiknowledge inference, accelerating knowledge discovery through three pivotal applications. To enhance user experience, we seamlessly integrated a sophisticated large language model that provides textual interpretations for each subgraph, bridging the gap between structured graphs and language expressions. With its comprehensive knowledge graph and user-centric applications, CPMKG serves as a valuable resource for clinical research, offering drug information tailored to personalized genetic profiles, syndromes, and phenotypes. Database URL: https://www.biosino.org/cpmkg/.

Genetic networks suggest Asperger’s syndrome as a distinct subtype of autism spectrum disorders

BackgroundThe Diagnostic and Statistical Manual of Mental Disorders (DSM-V) issued new diagnostic criteria for autism spectrum disorders (ASD) which resulted in missing the diagnosis of some cases of Asperger’s syndrome (AS). This negatively affected the support received by those affected. In this study, we explored if AS could be biologically stratified from the broader spectrum through a gene co-expression network preservation analysis. MethodsWe analysed the GEO microarray data of 24 individuals with Asperger’s syndrome and 72 individuals with autism. Then, we used a weighted gene co-expression network (WGCNA) pipeline to construct gene co-expression networks. We explored whether these modules share the same co-expression patterns between autism and Asperger’s syndrome using network preservation analysis. ResultsOur results showed that all co-expression modules of autism are preserved into the Asperger’s syndrome. However, three modules of Asperger’s syndrome out of 30 modules were not preserved in autism.Gene enrichment analysis revealed that these modules were involved in chromatin remodelling, immune and neuroinflammatory response, synaptic and neuronal development. Brain enrichment analysis showed significant downregulation of neurodevelopment genes in different brain regions associated with impaired social recognition in Asperger’s syndrome. ConclusionsThe identified genetic and molecular profiles suggest that Asperger’s syndrome, despite sharing numerous similarities with autism, possesses a distinct genetic profile that makes it a distinct subtype of autism. This distinction could have significant implications for the management and treatment strategies tailored to individuals with Asperger’s syndrome.

Combined Analysis of Human and Experimental Rat Samples Identified Biomarkers for Ischemic Stroke.

The genetic transcription profile and underlying molecular mechanisms of ischemic stroke (IS) remain elusive. To address this issue, four mRNA and one miRNA expression profile of rats with middle cerebral artery occlusion (MCAO) were acquired from the Gene Expression Omnibus (GEO) database. A total of 780 differentially expressed genes (DEGs) and 56 miRNAs (DEMs) were screened. Gene set and functional enrichment analysis revealed that a substantial number of immune-inflammation-related pathways were abnormally activated in IS. Through weighted gene co-expression network analysis, the turquoise module was identified as meaningful. By taking the intersection of the turquoise module genes, DEM-target genes, and all DEGs, 354 genes were subsequently obtained as key IS-related genes. Among them, six characteristic genes were identified using the least absolute shrinkage and selection operator. After validation with three external datasets, transforming growth factor beta 1 (Tgfb1) was selected as the hub gene. This finding was further confirmed by gene expression pattern analysis in both the MCAO model rats and clinical IS patients. Moreover, the expression of the hub genes exhibited a negative correlation with the modified Rankin scale score (P < 0.05). Collectively, these results expand our knowledge of the genetic profile and molecular mechanisms involved in IS and suggest that the Tgfb1 gene is a potential biomarker of this disease.

Integrated nasopharyngeal airway metagenome and asthma genetic risk endotyping of severe bronchiolitis in infancy and risk of childhood asthma.

Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. However, little is known about its biologically distinct subgroups based on the integrated metagenome and asthma genetic risk signature and their longitudinal relationships with asthma development. In a multi-center prospective cohort study of infants with severe bronchiolitis (i.e., bronchiolitis requiring hospitalization), we profiled nasopharyngeal airway metagenome and virus at hospitalization, and calculated the polygenic risk score of asthma. Using similarity network fusion clustering approach, we identified integrated metagenome-asthma genetic risk endotypes. We also examined their longitudinal association with the risk of developing asthma by age six years. Of 450 infants with bronchiolitis (median age, 3 months), we identified five distinct endotypes-characterized by their nasopharyngeal metagenome, virus, and asthma genetic risk profiles. Compared with endotype A infants (who clinically resembled "classic" bronchiolitis), endotype E infants (characterized by a high abundance of H. influenzae, high proportion of RV-A and RV-C infections, and high asthma genetic risk) had a significantly higher risk for developing asthma (35.9% versus 16.7%; ORadj, 2.24; 95%CI, 1.02-4.97; p=0.046). The pathway analysis showed that endotype E had enriched microbial pathways (e.g., glycolysis, L-lysine, arginine metabolism) and host pathways (e.g., IFNs, IL-6/JAK/STAT3, fatty acids, MHC, and immunoglobin-related) (FDR<0.05). Additionally, endotype E had a significantly higher proportion of neutrophils (FDR<0.05). In this multi-center prospective cohort study of infant bronchiolitis, the clustering analysis of integrated-omics data identified biologically distinct endotypes with differential risks for developing asthma.

Impact of Global Warming on Cancer Development: A Review of Environmental Carcinogens and Human Immunogenetics

This paper examines the impact of global warming on cancer development, specifically focusing on the intensified effects of environmental carcinogens such as ultraviolet (UV) radiation and air pollutants. Our review elucidates the intricate interplay between global warming, ecological carcinogens, human immunogenetics, and cancer susceptibility. The analysis highlights the exacerbating effects of rising temperatures and changes in atmospheric conditions on exposure to UV radiation and air pollutants, including particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), nitrogen dioxide (NO2), nitrogen oxides (NOx), and ground-level ozone (O3). Furthermore, the study explores the pivotal role of human immunogenetics in modulating individual responses to carcinogen exposure and shaping cancer susceptibility and progression. Genetic variations in key immune-related genes and their influence on the interplay between environmental carcinogens and cancer development are discussed. The paper underscores the importance of longitudinal cohort studies, integrative approaches, and interdisciplinary collaborations to advance our understanding of the complex interactions between global warming, environmental carcinogens, human immunogenetics, and cancer biology. Additionally, evidence-based public health interventions targeting environmental carcinogens and personalized prevention strategies based on genetic susceptibility profiles and environmental exposure assessments are proposed to address the growing challenges of environmentally induced cancers.

Pomological and Molecular Characterization of Apple Cultivars in the German Fruit Genebank.

Traditional varieties are a valuable tool in modern apple breeding. However, the use of synonyms and missing source documentation hinder an effective identification and conservation of relevant cultivars. During several projects, the authenticity and diversity of the apple cultivar collection of the German Fruit Genebank (GFG) was evaluated extensively. The trueness-to-type of 7890 apple trees was assessed on a pomological and molecular level. Pomological evaluations were performed by at least two experienced experts to identify the original cultivar names. On the molecular level, a set of 17 SSR markers was used to determine a unique genetic profile for each apple cultivar. The pomological and molecular characterization was expressed in terms of a comprehensive trueness-to-type criterion and the results were previously published as a well-curated dataset. In this study, the published dataset was analyzed to evaluate the quality and diversity of the apple collection of the GFG and highlight new findings based on phylogenetic and parentage analysis. The dataset contains 1404 unique genetic profiles corresponding to unambiguous cultivar names. Of these 1404 cultivars, 74% were assessed as true-to-type. The collection of diploid apple cultivars showed a high degree of expected heterozygosity (Hexp = 0.84). Genetic diversity in terms of year and location of origin was investigated with a STRUCTURE analysis. It was hypothesized that genetic diversity might decline overtime due to restrictive breeding programs. The results showed a shift dynamic between older and newer cultivars in one specific cluster, but no significant decrease in genetic diversity was observed in this study. Lastly, a parentage analysis was performed to check parental relationships based on historical research. Out of 128 parent-child trios, 110 trios resulted in significant relationships and reconfirmed the information from the literature. In some cases, the information from the literature was disproven. This analysis also allowed for readjusting the trueness-to-type criteria for previously undetermined cultivars. Overall, the importance of authenticity evaluations for gene bank cultivars was highlighted. Furthermore, the direct use of the dataset was shown by relevant investigations on the genetic diversity and structure of the apple cultivar collections of the GFG.

Pharmacophylogenetic insights into Scutellaria strigillosa Hemsl.: chloroplast genome and untargeted metabolomics, quantitative analysis and antibacterial analysis.

Scutellaria strigillosa Hemsl., known for its traditional use in Chinese herbal medicine, is valued for heat-clearing and detoxifying, promoting diuresis, reducing swelling, alleviating pain, and preventing miscarriage. Despite its historical use, comprehensive studies on pharmacophylogenetic analysis, including genetic and chemical profiles and the antimicrobial activity of S. strigillosa are still lacking. Understanding these aspects is crucial for fully realizing its therapeutic potential and ensuring sustainable use. This study aims to elucidate these aspects through comparative genomics, metabolomics, and antimicrobial assays with Scutellaria baicalensis Georgi and Scutellaria barbata D. Don. The chloroplast genome of S. strigillosa was assembled, measuring 152,533 bp, and revealing a high degree of conservation, especially in the protein-coding regions, and identified four regions trnK(UUU)-rps16, trnN(GUU)-trnR(ACG), accD-psaI, psbE-petL) of variability that could serve as phylogenetic markers. The phylogenetic analysis revealed a closer genetic relationship of S. strigillosa with S. tuberifera and S. scordifolia than traditionally classified, suggesting a need for taxonomic reevaluation within the genus. UPLC-Q-TOF-MS analysis in negative ion mode was used to explore the chemical diversity among these species, revealing distinct variations in their chemical compositions. S. strigillosa shared a closer chemical profile with S. barbata, aligning with phylogenetic findings. Metabolomic identification through Progenesis QI software resulted in the tentative identification of 112 metabolites, including a substantial number of flavonoids, diterpenoids, iridoid glycosides, phenylethanoid glycosides, and others. HPLC analysis further detailed the concentrations of 12 actives across the species, highlighting the variation in compound content. S. strigillosa shows antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, similar to S. baicalensis root extracts. This research enhances the understanding of the phylogenetic and phytochemical profiles and the antibacterial activity of S. strigillosa, offering new insights into its medicinal properties. The findings suggest a need for taxonomic reevaluation within the genus and underscore the potential antibacterial activity of S. strigillosa for therapeutic applications. Further studies are encouraged to explore its full medicinal potential and contribute to the sustainable development of Scutellaria species.

Targeted Therapies in Pancreatic Cancer: A New Era of Precision Medicine.

Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality in the United States, presents significant treatment challenges due to its late diagnosis and poor prognosis. Despite advances, the five-year survival rates remain dismally low, with only a fraction of patients eligible for potentially curative surgical interventions. This review aims to comprehensively examine the current landscape of targeted therapies in PDAC, focusing on recent developments in precision medicine approaches. We explore various molecular targets, including KRAS mutations, DNA damage repair deficiencies, mismatch repair pathway alterations, and rare genetic fusions. The review discusses emerging therapies, such as PARP inhibitors, immune checkpoint inhibitors, and novel targeted agents, like RET and NTRK inhibitors. We analyze the results of key clinical trials and highlight the potential of these targeted approaches in specific patient subgroups. Recent developments in PDAC research have emphasized precision oncology, facilitated by next-generation sequencing and the identification of genetic and epigenetic alterations. This approach tailors treatments to individual genetic profiles, improving outcomes and reducing side effects. Significant strides have been made in classifying PDAC into various subtypes, enhancing therapeutic precision. The identification of specific mutations in genes like KRAS, along with advancements in targeted therapies, including small molecule inhibitors, offers new hope. Furthermore, emerging therapies targeting DNA repair pathways and immunotherapeutic strategies also show promising results. As research evolves, integrating these targeted therapies with conventional treatments might improve survival rates and quality of life for PDAC patients, underscoring the shift towards a more personalized treatment paradigm.

Genetic profile of progressive myoclonic epilepsy in Mali reveals novel findings.

Progressive myoclonic epilepsy (PME) is a group of neurological disorders characterized by recurrent myoclonic seizures with progressive neurological deterioration. We investigated the genetics of three unrelated patients with PME from Mali, a country in sub-Saharan Africa highly underrepresented in genetic and genomic research. Participants were carefully examined and phenotyped. DNA was obtained for genetic analysis including whole exome sequencing (WES). In silico prediction tools and ACMG criteria were used to assess the deleteriousness of putative candidate variants. Pedigree analysis suggests autosomal recessive inheritance patterns for one family and sporadic forms of PME for the two other cases. WES identified novel homozygous missense variants in all the three patients, one each for NHLRC1, EPM2A, and NEU1. The sequence variants segregated with PME in each family and in silico studies including protein 3D structures, CADD scores and ACMG criteria suggested that they were damaging. PME is a group of clinically heterogeneous neurological disorders. Most reported cases in the literature are from European background with only a few cases described in North Africa. We report here novel pathogenic variants in three different genes causing PME phenotypes in three unrelated Malian patients, suggesting that genetic studies of underrepresented populations may expand the genetic epidemiology of PME. These findings also emphasize the need for inclusive genetic research to ensure a more targeted diagnostic and therapeutic approaches for diverse patient populations.

Spinocerebellar Ataxia in Brazil: A Comprehensive Genotype - Phenotype Analysis.

Spinocerebellar ataxias (SCAs) are a diverse group of hereditary neurodegenerative disorders characterized by progressive degeneration of the cerebellum and other parts of the nervous system. In this study, we examined the genotype‒phenotype correlations in SCAs within the Brazilian population by leveraging a comprehensive dataset of 763 individuals from SARAH Network of Rehabilitation Hospitals. Using a retrospective, cross-sectional, observational, multicentric approach, we analysed medical records and conducted standardized molecular testing to explore epidemiological characteristics, clinical manifestations, and genetic profiles of SCAs in Brazil. Our findings revealed the predominance of SCA3, followed by SCA7 and SCA2, which aligns with global trends and reflects the specific genetic landscape of Brazil. A significant inverse relationship between the age of symptom onset and CAG repeat length in the mutated allele was observed across SCAs 2, 3, and 7. This study also highlights a trend towards paternal inheritance in SCA2 and details the distribution of CAG repeat expansions, which correlates larger expansions with earlier onset and specific symptomatology. This extensive analysis underscores the critical importance of genetic testing in the diagnosis and management of SCAs and enlightens the intricate genotype‒phenotype interplay within a genetically diverse population. Despite certain limitations, such as potential selection bias and the retrospective nature of the study, our research provides invaluable insights into the prevalence, genetic underpinnings, and clinical variability of SCAs in Brazil. We suggest a broader demographic scope and investigations into nonmotor symptoms in future studies to obtain a more comprehensive understanding of SCAs.

Rapid genome-wide profiling of DNA methylation and genetic variation using guide positioning sequencing (GPS).

Whole-genome bisulfite sequencing (WGBS) has been extensively utilized for DNA methylation profiling over the past decade. However, it has shown limitations in terms of high costs and inefficiencies. The productivity and accuracy of DNA methylation detection rely critically on the optimization of methodologies and the continuous refinements of related sequencing platforms. Here, we describe a detailed protocol of guide positioning sequencing (GPS), a bisulfite-based, location-specific sequencing technology designed for comprehensive DNA methylation characterization across the genome. The fundamental principle of GPS lies in the substitution of dCTP with 5-methyl-dCTP (5mC) at the 3'-end of DNA fragments by T4 DNA polymerase, which protects cytosines from bisulfite conversion to preserve the integrity of the base composition. This alteration allows the 3'-end to independently facilitate genetic variation profiling and guides the 5'-end, enriched with methylation information, to align more rapidly to the reference genome. Hence, GPS enables the concurrent detection of both genetic and epigenetic variations. Additionally, we provide an accessible description of the data processing, specifically involving certain software and scripts. Overall, the entire GPS procedure can be completed within a maximum of 15days, starting with a low initial DNA input of 100-500ng, followed by 4-5days for library construction, 8-10days for high-throughput sequencing (HTS) and data analysis, which can greatly facilitate the promotion and application of DNA methylation detection, especially for the rapid clinical diagnosis of diverse disease pathologies associated with concurrent genetic and epigenetic variations.