Genetic Implications Research Articles

Management of pediatric thyroid carcinoma.

The incidence of thyroid carcinoma is increasing among children and adolescents, particularly in female individuals. Children and adolescents require special considerations in management as the molecular genetics of pediatric thyroid tumors are inherently different from their adult counterparts. The increased risk of malignancy, nodal metastases, and pulmonary metastases in pediatric patients warrants pediatric-specific management recommendations and pediatric-specific multidisciplinary teams. This article highlights the molecular origins of pediatric thyroid carcinoma and the implications of tumor genetics for the course of disease and treatment considerations. We highlight specific surgical considerations to optimize outcomes while minimizing lifelong risks of vocal paralysis and hypoparathyroidism. The landscape of treatment options is rapidly evolving with development of sophisticated molecular approaches to understand the genetic landscape, and this review features updated recommendations and systemic treatment options for the management of pediatric thyroid malignancy. Pediatric thyroid carcinoma is a lifelong burden and the treatment tailored to optimize outcomes minimizes long-term risks of treatments, surgery, radiation and targeted systemic therapies. Multidisciplinary teams that treat pediatric thyroid carcinoma should focus surgical experience and use the most updated guidelines and treatments available, particularly considering the landscape of molecular genetics in pediatric thyroid carcinoma.

Exploring the genetic implications of demographic dynamics in Jammu and Kashmir using autosomal STRs.

The Union Territory of Jammu and Kashmir has always been a point of contention among India, Pakistan, and China for various reasons. This region has great significance historically due to its geography and ethnic diversity. However, a comprehensive genetic study providing the genetic landscape of Jammu and Kashmir was lacking until now. In this study, we analysed 21 hyper-variable autosomal STR loci of 694 individuals from Jammu and Kashmir and compared them with neighbouring populations to explore the genetic implications of demographic dynamics that have taken place in this region. Our findings suggest that the population of Jammu and Kashmir is a genetic mixture of two major clines, northern and southern, that correspond with the variation in geography, linguistics, and demography of the region. Broadly, the gene flow into the southern cline appears to be in historical times perhaps as a result of the spread of Gurjars, Dogri language and invasions of Mongols. However, the arrival of ancient nomadic tribes into this region may belong to the time depth of the arrival of pastoralist communities in this region. As a future perspective, a comprehensive study including samples from individual tribes will provide fine-scale structure of the gene pool of Jammu and Kashmir.

The next frontier in multiple sclerosis therapies: Current advances and evolving targets.

Recent advancements in research have significantly enhanced our comprehension of the intricate immune components that contribute to multiple sclerosis (MS) pathogenesis. By conducting an in-depth analysis of complex molecular interactions involved in the immunological cascade of the disease, researchers have successfully identified novel therapeutic targets, leading to the development of innovative therapies. Leveraging pioneering technologies in proteomics, genomics, and the assessment of environmental factors has expedited our understanding of the vulnerability and impact of these factors on the progression of MS. Furthermore, these advances have facilitated the detection of significant biomarkers for evaluating disease activity. By integrating these findings, researchers can design novel molecules to identify new targets, paving the way for improved treatments and enhanced patient care. Our review presents recent discoveries regarding the pathogenesis of MS, highlights their genetic implications, and proposes an insightful approach for engaging with newer therapeutic targets in effectively managing this debilitating condition.

Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner

Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer’s disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying the P522R mutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, the P522R mutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies.

A Comparative Study on Different Gotra Marriages Versus Inter-caste and Inter-religious Marriages: Cultural, Social, and Genetic Implications

This paper investigates the cultural, social, and genetic implications of different Gotra marriages versus inter-caste and inter-religious marriages. Utilizing a multidisciplinary approach, including forensic psychology, DNA fingerprinting, and forensic genetics, this comparative study explores the psychological, social, and genetic diversity in these forms of marriage. A review of literature, methodological approaches in genetic forensics, and forensic psychology are used to understand how societal norms, mental health, and genetic diversity intersect in these marriage types.

Potential of Ex Situ Conservation Strains Revealed by Genetic Analysis of Oceanic Islands' Endangered Species Pittosporum parvifolium.

The Ogasawara Islands, representing an oceanic island ecosystem in Japan, have a notably high rate of endemic species akin to other oceanic islands globally. Pittosporum parvifolium is a critically endangered shrub with only four remaining individuals in its natural habitat on the Ogasawara Islands. Current conservation efforts encompass both insitu and ex situ approaches for P. parvifolium. However, these efforts face challenges stemming from the lack of critical conservation information. Therefore, we explored P. parvifolium's genetic diversity and implications for conservation. We utilized simple sequence repeat markers to scrutinize genetic diversity within both insitu and ex situ populations, revealing notably rich diversity among both. The insitu genetic diversity was significantly high despite the few extant individuals. In addition, many of the ex situ peculiar genotypes were absent in individuals conserved insitu. This investigation also provides insights into the reproductive strategies and combinations of selfing and outcrossing. The results of the present study recommend conservation to maximize genetic diversity in P. parvifolium by promoting cross-pollination among insitu individuals and by introducing individuals with unique genotypes into ex situ stocks.

Heritability and genetic contribution analysis of structural-functional coupling in human brain

Abstract The flow of functional connectivity (FC) is thought to be supported by white matter structural connectivity (SC). While research on the correlations between SC and FC (SC-FC coupling) has progressed, the genetic implications of SC-FC coupling have not been thoroughly examined. Traditionally, SC-FC coupling investigations utilize predefined atlases. Here, we adopted an atlas-free SC-FC coupling built on the high-resolution white surface (the interface of white matter and gray matter) to uncover common genetic variations. Leveraging data from the Human Connectome Project, we demonstrated considerable heritability in areas within the early and intermediate visual cortex and across dorsal-attention, language, and somatomotor functional networks. We detected 334 genetic loci (spanning 234 cytogenetic bands) linked to SC-FC coupling (P < 1.26 × 10−11), notably in cingulo-opercular, somatomotor, and default mode networks. Using an external dataset from the Adolescent Brain Cognitive Development study, we confirmed 187 cytogenetic bands associated with SC-FC coupling across 22 brain regions (P < 1 × 10-5). Genetic correlation analyses revealed high genetic interrelatedness for SC-FC coupling in neighboring regions. Furthermore, it showed genetic correlations with a spectrum of complex traits, encompassing various neurological and psychiatric conditions. In essence, our study paves the way towards deciphering the genetic interplay between structural and functional connectivity of the brain.

Investigating the effect of polygenic background on epilepsy phenotype in ‘monogenic’ families

Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies. We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models. 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR=1.39, 95% CI 1.08, 1.80, padj=0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of+0.19 higher than relatives with a milder phenotype (padj=0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj=0.0010), the effect was not significant for SCN1B p.Cys121Trp. We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients. National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Genetic variation, structural analysis, and virulence implications of BimA and BimC in clinical isolates of Burkholderia pseudomallei in Thailand

Melioidosis is a life-threatening tropical disease caused by an intracellular gram-negative bacterium Burkholderia pseudomallei. B. pseudomallei polymerizes the host cell actin through autotransporters, BimA, and BimC, to facilitate intracellular motility. Two variations of BimA in B. pseudomallei have been reported previously: BimABp and BimA B. mallei-like (BimABm). However, little is known about genetic sequence variations within BimA and BimC, and their potential effect on the virulence of B. pseudomallei. This study analyzed 1,294 genomes from clinical isolates of patients admitted to nine hospitals in northeast Thailand between 2015 and 2018 and performed 3D structural analysis and plaque-forming efficiency assay. The genomic analysis identified 10 BimABp and 5 major BimC types, in the dominant and non-dominant lineages of the B. pseudomallei population structure. Our protein prediction analysis of all BimABp and major BimC variants revealed that their 3D structures were conserved compared to those of B. pseudomallei K96243. Sixteen representative strains of the most distant BimABp types were tested for plaque formation and the development of polar actin tails in A549 epithelial cells. We found that all isolates retained these functions. These findings enhance our understanding of the prevalence of BimABp and BimC variants and their implications for B. pseudomallei virulence.

Classic Kaposi sarcoma: Diagnostics, treatment modalities, and genetic implications - A review of the literature.

Classic Kaposi sarcoma (CKS) is a rare vascular disease mainly found in populations of Mediterranean origin. The pathogenesis involves Human Herpes Virus 8 (HHV8) and genetic mutations such as SNP309 in the MDM2 gene. The recently discovered BPTF mutation in cells of CKS patients demonstrated higher latency-associated nuclear antigen (LANA) staining and altered vital transcriptomics, implicating a potential role in tumorigenesis. This review explores the genetic underpinnings and treatments for CKS. A comprehensive literature search was conducted from 2004 to 2024, yielding 70 relevant papers. Ongoing clinical trials investigating novel treatments such as talimogene and abemaciclib were included in the search and presented in the results. Clinical diagnosis and treatment can be challenging as the number of studies on CKS and treatment modalities is limited. Treatment strategies vary by disease stage, with local therapies like surgical intervention and radiation therapy recommended for early stages, while systemic therapies are considered in cases of systemic disease. While advancements in CKS treatment offer hope, further studies on immunotherapy are warranted to broaden the therapeutic options, such as anti-bromodomain or BPTF-targeted therapy.

Exploring the effects of simulated microgravity on esophageal cancer cells: insights into morphological, growth behavior, adhesion, and genetic damage.

The exploration of microgravity has garnered substantial scholarly attention due to its potential to offer unique insights into the behavior of biological systems. This study presents a preliminary investigation into the effects of simulated microgravity on esophageal cancer cells, examining various aspects such as morphology, growth behavior, adhesion, inhibition rate, and DNA damage. To achieve this, a novel microgravity simulator named "Gravity Challenge" was utilized for its effectiveness in minimizing external influences that could compromise microgravity conditions. The international cell line SK-GT-4 was utilized as the focal point of this investigation. Results revealed noticeable alterations in the growth behavior of cancer cells following exposure to simulated microgravity for 24 h, characterized by a loss of adhesion properties compared to control cells. Concurrently, cell viability exhibited a decline, as evidenced by cytotoxicity testing. Furthermore, the comet assay test demonstrated that cells subjected to microgravity simulation experienced a higher incidence of DNA damage compared to their control counterparts. In conclusion, this comprehensive examination of the impact of simulated microgravity on esophageal cancer cells extends beyond morphological changes, delving into genetic implications through observed DNA damage. The diminished vitality of cells under microgravity conditions underscores the multifaceted effects on cellular behavior in response to environmental variations. These findings represent a significant step towards understanding the dynamics of cancer cells, laying the groundwork for future research aimed at identifying potential therapeutic strategies for this disease.

“EPIDERMÓLISE BOLHOSA DISTRÓFICA RECESSIVA.”

This study addresses Recessive Dystrophic Epidermolysis Bullosa (RDEB), a rare genetic disorder characterized by extreme fragility of the skin and mucous membranes. The objective is to explore the clinical, genetic, and psychosocial implications for patients with RDEB, with an emphasis on emerging therapies such as gene and biotechnological interventions. Using a qualitative methodology and a literature review from reputable scientific databases, the study will analyze the effectiveness of these new therapies and their impact on patients’ quality of life. The main expected outcomes include validating the new therapies and formulating guidelines to improve the management of RDEB. It is concluded that emerging therapeutic approaches have the potential to transform the prognosis of RDEB, although further studies are necessary to consolidate these strategies.

Understanding Down Syndrome: A Systematic Review of Genetic, Clinical, and Cognitive Implications

Down syndrome (DS) is the most common chromosomal disorder, primarily caused by trisomy 21, and is associated with a range of genetic, clinical, and cognitive challenges. This systematic review aims to provide a comprehensive understanding of these aspects by synthesizing recent research on the genetic mechanisms underlying DS, its common clinical manifestations, and the cognitive impairments often observed in affected individuals. Genetic studies highlight the complexity of trisomy 21 and its impact on phenotypic variability. Clinically, DS is associated with distinct physical features, congenital heart defects, and a predisposition to conditions such as thyroid disorders and leukemia. Cognitive impairments, including intellectual disability and early-onset Alzheimer's disease, present significant challenges for individuals with DS, often requiring early intervention and lifelong support. Recent advancements in medical care, therapeutic interventions, and educational strategies have improved quality of life and life expectancy for individuals with DS. This review identifies gaps in the current literature, such as the need for more personalized therapeutic approaches based on genetic variability, and highlights areas for future research to further improve outcomes for individuals with Down syndrome.

Exploring High-Penetrance Genes in Breast Cancer Associated Genetic Syndromes: Insights into Genetic Predisposition and Clinical Implications

Exploring High-Penetrance Genes in Breast Cancer Associated Genetic Syndromes: Insights into Genetic Predisposition and Clinical Implications

Inherited PURA Pathogenic Variant Associated With a Mild Neurodevelopmental Disorder.

Purine-rich element-binding protein alpha (PURA) regulates gene expression and is ubiquitously expressed with an enrichment in neural tissues. Pathogenic variants in PURA cause the neurodevelopmental disorder PURA syndrome that has a variable phenotype but typically comprises moderate-to-severe global developmental delay, intellectual disability, early-onset hypotonia and hypothermia, epilepsy, feeding difficulties, movement disorders, and subtle facial dysmorphism. Speech is reportedly absent in most, but the specific linguistic phenotype is not well described. We used genome sequencing to identify a pathogenic gene variant as part of a study of children ascertained for severe primary speech disorder in the absence of moderate or severe ID. The novel PURA c.296G>T (p.Arg99Leu) pathogenic missense variant segregated in the female proband and her affected mother. The proband had dysarthria; phonological disorder; and severe receptive and expressive language impairment, borderline intellect, attention difficulties, oropharyngeal dysmotility, and dysmorphic facial features. Her mother had dysarthria, moderate receptive language impairment, and borderline intellect. Both the proband and her mother completed mainstream schooling with classroom support. This is the first inherited PURA pathogenic germline variant in over 600 unrelated families documented on ClinVar or reported in the literature. PURA testing should be considered in families with primary speech disorder and borderline intellectual disability, given the specific genetic counseling implications.

Genetic and immunological implications in fibromyalgia: A Literature Review

Fibromyalgia (FM), a musculoskeletal condition characterized by widespread pain and numerous associated symptoms, is a complex disorder with uncertain etiology and pathogenesis. Most of the patients suffering from this syndrome are undiagnosed due to a lack of standard diagnostic criteria. Recent studies have shown the involvement of immune dysfunction and various pro-inflammatory cytokines in FM. Since there is so much uncertainty regarding the pathogenesis of FM, treatment modalities are very limited and ineffective. This review aimed to analyze the immunological mechanisms behind FM, attempting to deepen the understanding of its pathogenesis. Additionally, the review elucidates FM's associations with autoimmune diseases, highlighting shared pathophysiological mechanisms and overlapping symptoms. We synthesized current literature available on Google Scholar, PubMed, Springer, and Web of Science, the review explored the intricate interactions between genetic predisposition, immune dysregulation, and environmental factors in FM pathogenesis. The inclusion criteria prioritized studies focusing on the immunological aspect of FM. In conclusion, immune dysfunction has a role to play in the pathogenesis of FM, and immunomodulatory therapies have proven to be beneficial in the treatment of FM. Genetic variants, epigenetic modifications, and gut microbiome alterations are potential triggers for immune system dysfunction, contributing to the manifestation and exaggeration of FM symptoms. This review provided a comprehensive resource for researchers and clinicians, a guide for future investigations and clinical management towards improved outcomes and enhanced quality of life for individuals with FM.

Targeted and complete genomic sequencing of the major histocompatibility complex in haplotypic form of individual heterozygous samples.

The human major histocompatibility complex (MHC) is a ∼4 Mb genomic segment on Chromosome 6 that plays a pivotal role in the immune response. Despite its importance in various traits and diseases, its complex nature makes it challenging to accurately characterize on a routine basis. We present a novel approach allowing targeted sequencing and de novo haplotypic assembly of the MHC region in heterozygous samples, using long-read sequencing technologies. Our approach is validated using two reference samples, two family trios, and an African-American sample. We achieved excellent coverage (96.6%-99.9% with at least 30× depth) and high accuracy (99.89%-99.99%) for the different haplotypes. This methodology offers a reliable and cost-effective method for sequencing and fully characterizing the MHC without the need for whole-genome sequencing, facilitating broader studies on this important genomic segment and having significant implications in immunology, genetics, and medicine.

Genetic Implications for Cancer Management: The Changing Landscape of Poly (ADP-ribose) Polymerase Inhibitor Indications in the Treatment of Ovarian Cancer.

Between December 2014 and May 2020, the United States Food and Drug Administration approved 9 indications for poly (ADP-ribose) polymerase (PARP) inhibitor use in ovarian cancer. Between June 2022 and September 2022, all 3 indications for PARP inhibitor treatment of recurrent ovarian cancer were withdrawn. Between November 2022 and September 2023, all 3 indications for PARP inhibitor maintenance therapy in recurrent ovarian cancer were restricted. The 3 indications for PARP inhibitor maintenance therapy in newly diagnosed advanced ovarian cancer are unchanged. This article reviews the timelines and data leading to regulatory changes for PARP inhibitor use in ovarian cancer in the United States.

World-class amethyst-agate geodes from Los Catalanes, Northern Uruguay: genetic implications from fluid inclusions and stable isotopes

AbstractThe amethyst and agate geodes from the Los Catalanes Gemmological District in Uruguay represent one of the main deposits of its kind worldwide. The geometry of the deposit is horizontal, with an irregular distribution of amethyst geodes within the upper level of the basalt lava flows and shows strong variations in their abundance, as well as quality, geometry, and shape. Reliable exploration guides are scarce, and the limited knowledge of the geological parameters controlling its occurrence makes exploration unpredictable, leading to inaccurate reserve estimation. Based on cutting-edge methods including nucleation-assisted microthermometry of one-phase fluid inclusions and determination of triple oxygen isotope in silicates and carbonates, as well as analysis of geode-hosted water and groundwater, we estimate the crystallisation temperatures in the range between 15 and 60 °C. These low temperatures point to amethyst crystallisation after the emplacement of the complete basalt pile. The mineralising fluid shows isotopic signatures consistent with meteoric water and very low salinities from pure water up to rarely over 3 wt% NaCl-eq., likely sourced from the groundwater hosted in the aquifers in the basaltic sequence and underlying units. Based on the insights provided by the new data, we propose the combination of open- and closed-system crystallisation inside pre-existing cavities due to the episodic infiltration of meteoric water in a rather stable geological context.

Identification of the genetic determinants and clinical implications of bone marrow adiposity using deep learning in the uk biobank

Identification of the genetic determinants and clinical implications of bone marrow adiposity using deep learning in the uk biobank