Genetic Landscape Research Articles

Genetic analysis of 106 sporadic cases with hearing loss in the UAE population

BackgroundHereditary hearing loss is a rare hereditary condition that has a significant presence in consanguineous populations. Despite its prevalence, hearing loss is marked by substantial genetic diversity, which poses challenges for diagnosis and screening, particularly in cases with no clear family history or when the impact of the genetic variant requires functional analysis, such as in the case of missense mutations and UTR variants. The advent of next-generation sequencing (NGS) has transformed the identification of genes and variants linked to various conditions, including hearing loss. However, there remains a high proportion of undiagnosed patients, attributable to various factors, including limitations in sequencing coverage and gaps in our knowledge of the entire genome, among other factors. In this study, our objective was to comprehensively identify the spectrum of genes and variants associated with hearing loss in a cohort of 106 affected individuals from the UAE.ResultsIn this study, we investigated 106 sporadic cases of hearing impairment and performed genetic analyses to identify causative mutations. Screening of the GJB2 gene in these cases revealed its involvement in 24 affected individuals, with specific mutations identified. For individuals without GJB2 mutations, whole exome sequencing (WES) was conducted. WES revealed 33 genetic variants, including 6 homozygous and 27 heterozygous DNA changes, two of which were previously implicated in hearing loss, while 25 variants were novel. We also observed multiple potential pathogenic heterozygous variants across different genes in some cases. Notably, a significant proportion of cases remained without potential pathogenic variants.ConclusionsOur findings confirm the complex genetic landscape of hearing loss and the limitations of WES in achieving a 100% diagnostic rate, especially in conditions characterized by genetic heterogeneity. These results contribute to our understanding of the genetic basis of hearing loss and emphasize the need for further research and comprehensive genetic analyses to elucidate the underlying causes of this condition.

The Effect of Genetic Variants of SLC22A2 (rs662301 and rs315978) on the response to Metformin in type 2 Saudi diabetic patients

PurposeTo investigate the allelic and genotypic frequencies of the two genetic variations, NC_000006.12: g.160275887C > T (rs662301) and NC_000006.12:g.160231826 T > C (rs315978), in the SLC22A2 gene among the Saudi population. The primary goal is to elucidate potential associations with these genetic variations and the response to metformin therapy over 6 months to enhance our knowledge of the genetic basis of Type 2 Diabetes Mellitus (T2DM) and its clinical management in the Saudi population. Materials/Methods76 newly diagnosed T2DM patients, aged 30 to 60, of both sexes and Saudi origin, were treated with metformin monotherapy. Blood samples were collected before and after 6 months of therapy,80 healthy individuals were included as controls. Genomic DNA was extracted. Genotyping of the SLC22A2 genetic variations was performed using TaqMan® SNP Genotyping Assays. Binary logistic regression was utilized to evaluate how certain clinical parameters influence T2DM concerning the presence of SLC22A2 gene variants. ResultsAmong these patients, 73.3 % were responders, and 26.7 % were non-responders. For these variants, no statistically significant differences in genotype or allele frequencies were observed between responders and non-responders (p = 0.375 and p = 0.384 for rs662301; p = 0.473 and p = 0.481 for rs315978, respectively). For the SLC22A2 variant rs662301, the C/C genotype was significantly associated with increased T2DM risk with age and elevated HbA1c levels. Similarly, rs315978 revealed higher T2DM susceptibility and HbA1c elevation in C/C genotype carriers, specifically with advancing age compared to individuals with C/T and T/T genotypes. ConclusionThe study offers insights into the genetic landscape of T2DM in Saudi Arabia. Despite the absence of significant associations with treatment response, the study suggests potential age-specific associations, this highlights the complexity of the disease. This research underscores the necessity for expanded research, considering diverse populations and genetic factors, to develop personalized treatment approaches. This study serves as a foundation for future investigations into the Saudi population, recognizing the need for a larger sample size.

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment.

Chorea is a hyperkinetic movement disorder frequently observed in the pediatric population, and, due to advancements in genetic techniques, an increasing number of genes have been associated with this disorder. In genetic conditions, chorea may be the primary feature of the disorder, or be part of a more complex phenotype characterized by epileptic encephalopathy or a multisystemic syndrome. Moreover, it can appear as a persistent disorder (chronic chorea) or have an episodic course (paroxysmal chorea). Managing chorea in childhood presents challenges due to its varied clinical presentation, often involving a spectrum of hyperkinetic movement disorders alongside neuropsychiatric and multisystemic manifestations. Furthermore, during infancy and early childhood, transient motor phenomena resembling chorea occurring due to the rapid nervous system development during this period can complicate the diagnosis. This review aims to provide an overview of the main genetic causes of pediatric chorea that may manifest during infancy and early childhood, focusing on peculiarities that can aid in differential diagnosis among different phenotypes and discussing possible treatment options.

Exploring the Genetic Landscape of Tilia Spp. with Molecular and Statistical Tools

Exploring the Genetic Landscape of Tilia Spp. with Molecular and Statistical Tools

Genetic Landscape of SH3TC2 variants in Russian patients with Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease type 4C (CMT4C) OMIM#601596 stands out as one of the most prevalent forms of recessive motor sensory neuropathy worldwide. This disorder results from biallelic pathogenic variants in the SH3TC2 gene. Within a cohort comprising 700 unrelated Russian patients diagnosed with Charcot-Marie-Tooth disease, we conducted a gene panel analysis encompassing 21 genes associated with hereditary neuropathies. Among the cohort, 394 individuals exhibited demyelinating motor and sensory neuropathy. Notably, 10 cases of CMT4C were identified within this cohort. The prevalence of CMT4C among Russian demyelinating CMT patients lacking the PMP22 duplication is estimated at 2.5%, significantly differing from observations in European populations. In total, 4 novel and 9 previously reported variants in the SH3TC2 gene were identified. No accumulation of a major variant was detected. Three previously reported variants, c.2860C>T p. (Arg954*), p. (Arg658Cys) and c.279G>A p. (Lys93Lys), recurrently detected in unrelated families. Nucleotide alteration p. (Arg954*) is present in most of our patients (30%).

Application value of multi-gene mutation detection in the clinical management of pediatric papillary thyroid carcinoma: a preliminary exploration.

Thyroid cancer rarely occurs in children and adolescents. Molecular markers such as BRAF, RAS, and RET/PTC have been widely used in adult PTC. It is currently unclear whether these molecular markers have equivalent potential for application in pediatric patients. This study aims to explore the potential utility of a multi-gene conjoint analysis based on next-generation targeted sequencing for pediatric papillary thyroid carcinoma (PTC). The patients diagnosed with PTC (aged 18 years or younger) in the pediatrics department of Lishui District Hospital of Traditional Chinese Medicine were retrospectively screened. A targeted enrichment and sequencing analysis of 116 genes associated with thyroid cancer was performed on paraffin-embedded tumor tissues and paired paracancerous tissue of fifteen children (average age 14.60) and nine adults (average age 49.33) PTC patients. Demographic information, clinical indicators, ultrasonic imaging information and pathological data were collected. The Kendall correlation test was used to establish a correlation between molecular variations and clinical characteristics in pediatric patients. A sample of 15 pediatric PTCs revealed a detection rate of 73.33% (11/15) for driver gene mutations BRAF V600E and RET fusion. Compared to adult PTCs, the genetic mutation landscape of pediatric PTCs was more complex. Six mutant genes overlap between the two groups, and an additional seventeen unique mutant genes were identified only in pediatric PTCs. There was only one unique mutant gene in adult PTCs. The tumor diameter of pediatric PTCs tended to be less than 4cm (p<0.001), and the number of lymph node metastases was more than five (p<0.001). Mutations in specific genes unique to pediatric PTCs may contribute to the onset and progression of the disease by adversely affecting hormone synthesis, secretion, and action mechanisms, as well as the functioning of thyroid hormone signaling pathways. But, additional experiments are required to validate this hypothesis. BRAF V600E mutation and RET fusion are involved in the occurrence and development of adolescent PTC. For pediatric thyroid nodules that cannot be determined as benign or malignant by fine needle aspiration biopsy, multiple gene combination testing can provide a reference for personalized diagnosis and treatment by clinical physicians.

Transcriptomic alterations in host parasitoid wasps resulting in extended lifespan due to PpNSRV-1 infection

The parasitoid wasp Pteromalus puparum, a pivotal agent in agricultural ecosystem balance, experiences significant alterations in lifespan due to infection by the negative-sense single-stranded RNA virus PpNSRV-1. This study utilized RNA sequencing (RNA-seq) to investigate the genetic mechanism(s) driving lifespan extension in response to this virus. Lifespan analysis, combined with RNA-seq of nearly isogenic lines of infected and uninfected wasps, yields a comprehensive temporal expression profile aligned with the P. puparum genome. Despite a modest overall impact of PpNSRV-1 on gene expression, notable effects were observed on specific gene families, such as the SPOP genes and the cytochrome P450 family. Through Weighted Gene Co-expression Network Analysis (WGCNA), we identified connections between the green and greenyellow modules to viral infection traits, with further functional analyses highlighting the pivotal roles of the Hedgehog, autophagy, AMPK, mTOR, p53, and PI3K-Akt signaling pathways. RNA interference experiment targeting the SPOP gene PPU06594-RA confirmed its role in lifespan modulation, underscoring the importance of Hedgehog pathway in the host’s adaptive response. These insights not only elucidate the complex genetic landscape of host-virus interactions but also open avenues for innovative biological pest control strategies.

Whole genome sequences of 70 indigenous Ethiopian cattle

Indigenous animal genetic resources play a crucial role in preserving global genetic diversity and supporting the livelihoods of millions of people. In Ethiopia, the majority of the cattle population consists of indigenous breeds. Understanding the genetic architecture of these cattle breeds is essential for effective management and conservation efforts. In this study, we sequenced DNA samples from 70 animals from seven indigenous cattle breeds, generating about two terabytes of pair-end reads with an average coverage of 14X. The sequencing data were pre-processed and mapped to the cattle reference genome (ARS-UCD1.2) with an alignment rate of 99.2%. Finally, the variant calling process produced approximately 35 million high-quality SNPs. These data provide a deeper understanding of the genetic landscape, facilitate the identification of causal mutations, and enable the exploration of evolutionary patterns to assist cattle improvement and sustainable utilization, particularly in the face of unpredictable climate changes.

MmpR5 protein truncation and bedaquiline resistance in Mycobacterium tuberculosis isolates from South Africa: a genomic analysis

The antibiotic bedaquiline is a key component of new WHO regimens for drug-resistant tuberculosis; however, predicting bedaquiline resistance from bacterial genotypes remains challenging. We aimed to understand the genetic mechanisms of bedaquiline resistance by analysing Mycobacterium tuberculosis isolates from South Africa. For this genomic analysis, we conducted whole-genome sequencing of Mycobacterium tuberculosis samples collected at two referral laboratories in Cape Town and Johannesburg, covering regions of South Africa with a high prevalence of tuberculosis. We used the tool ARIBA to measure the status of predefined genes that are associated with bedaquiline resistance. To produce a broad genetic landscape of M tuberculosis in South Africa, we extended our analysis to include all publicly available isolates from the European Nucleotide Archive, including isolates obtained by the CRyPTIC consortium, for which minimum inhibitory concentrations of bedaquiline were available. Between Jan 10, 2019, and July, 22, 2020, we sequenced 505 M tuberculosis isolates from 461 patients. Of the 64 isolates with mutations within the mmpR5 regulatory gene, we found 53 (83%) had independent acquisition of 31different mutations, with a particular enrichment of truncated MmpR5 in bedaquiline-resistant isolates resulting from either frameshift mutations or the introduction of an insertion element. Truncation occurred across three Mtuberculosis lineages, and were present in 66% of bedaquiline-resistant isolates. Although the distributions overlapped, the median minimum inhibitory concentration of bedaquiline was 0·25 mg/L (IQR 0·12-0·25) in mmpR5-disrupted isolates, compared with 0·06 mg/L (0·03-0·06) in wild-type M tuberculosis. Reduction in the susceptibility of M tuberculosis to bedaquiline has evolved repeatedly across the phylogeny. In our data, we see no evidence that this reduction has led to the spread of a successful strain in South Africa. Binary phenotyping based on the bedaquiline breakpoint might be inappropriate to monitor resistance to this drug. We recommend the use of minimum inhibitory concentrations in addition to MmpR5 truncation screening to identify moderate increases in resistance to bedaquiline. US Centers for Disease Control and Prevention.

Whole exome sequencing analyses reveal novel genes in telomere length and their biomedical implications.

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.

Systems genomics of salinity stress response in rice.

Populations can adapt to stressful environments through changes in gene expression. However, the role of gene regulation in mediating stress response and adaptation remains largely unexplored. Here, we use an integrative field dataset obtained from 780 plants of Oryza sativa ssp. indica (rice) grown in a field experiment under normal or moderate salt stress conditions to examine selection and evolution of gene expression variation under salinity stress conditions. We find that salinity stress induces increased selective pressure on gene expression. Further, we show that trans-eQTLs rather than cis-eQTLs are primarily associated with rice's gene expression under salinity stress, potentially via a few master-regulators. Importantly, and contrary to the expectations, we find that cis-trans reinforcement is more common than cis-trans compensation which may be reflective of rice diversification subsequent to domestication. We further identify genetic fixation as the likely mechanism underlying this compensation/reinforcement. Additionally, we show that cis- and trans-eQTLs are under different selection regimes, giving us insights into the evolutionary dynamics of gene expression variation. By examining genomic, transcriptomic, and phenotypic variation across a rice population, we gain insights into the molecular and genetic landscape underlying adaptive salinity stress responses, which is relevant for other crops and other stresses.

Quantifying variations associated with dental caries reveals disparity in effect allele frequencies across diverse populations

BackgroundDental caries (DC) is a multifaceted oral condition influenced by genetic and environmental factors. Recent advancements in genotyping and sequencing technologies, such as Genome-Wide Association Studies (GWAS) have helped researchers to identify numerous genetic variants associated with DC, but their prevalence and significance across diverse global populations remain poorly understood as most of the studies were conducted in European populations, and very few were conducted in Asians specifically in Indians.AimThis study aimed to evaluate the genetic affinity of effect alleles associated with DC to understand the genetic relationship between global populations with respect to the Indian context.MethodologyThis present study used an empirical approach in which variants associated with DC susceptibility were selected. These variants were identified and annotated using the GWAS summary. The genetic affinity was evaluated using Fst.ResultsThe effect of allele frequencies among different populations was examined, revealing variations in allele distribution. African populations exhibited higher frequencies of specific risk alleles, whereas East Asian and European populations displayed distinct profiles. South Asian populations showed a unique genetic cluster.ConclusionOur study emphasises the complex genetic landscape of DC and highlights the need for population-specific research as well as validation of GWAS-identified markers in Indians before defining them as established candidate genes.

Bioinformatics and Gene Expression Omnibus Analysis of Key Candidate Genes and Pathways Associated with Femoral Head Necrosis

Background: Femoral head necrosis (FHN) is a debilitating bone disease affecting an estimated 8 million people worldwide. Although specific drugs for FHN have limitations, targeted therapies have shown promising results. The significance of this study is underscored by the high prevalence of FHN, the limitations of current treatments, and the potential of targeted drugs and natural compounds for effective therapeutic interventions. Objectives: This study aimed to explore the genetic landscape and associated pathways of FHN through bioinformatics analysis of Gene Expression Omnibus (GEO) data and molecular docking simulations targeting specific enzymes implicated in FHN. Methods: Differentially expressed genes (DEGs) in FHN samples were identified from GEO datasets, specifically accession number GSE123568 (Platform: GPL15207). Functional enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to identify enriched pathways and Gene Ontology (GO) terms. Additionally, a protein-protein interaction (PPI) network was constructed using the STITCH (search tool for interaction of chemicals) database, which helped identify top hub genes and proteins. Molecular docking was conducted against key proteins using compounds from the topical chinese herbal medicine (TCHM) database associated with FHN. Results: The study provided a comprehensive bioinformatics analysis of key candidate genes and pathways associated with FHN, which may serve as potential therapeutic targets. It was found that FHN is associated with mitogen-activated protein kinases (MAP4K4/ MAPK8/ MAPK9) and interleukins (IL1b/ IL19/ IL26). Molecular docking results showed strong interactions of traditional Chinese herbal compounds through hydrogen bonding and electrostatic interactions at the active sites of the top ten target proteins associated with FHN. Conclusions: The study confirmed that FHN is linked with enzymes such as mitogen-activated protein kinases (MAPKs), interleukins, tumor necrosis factors (TNFs), and VEGFA (vascular endothelial growth factor A). Molecular docking simulations demonstrated that hesperidin, naringin, and curcumin exhibit potent inhibition against key proteins involved in FHN. Future research will focus on elucidating the specific roles of genes associated with FHN and exploring potential therapeutic targets using natural compounds.

Sugemalimab in locally advanced and advanced Chinese NSCLC: A real-world retrospective study.

e20575 Background: Lung cancer is a major cause of cancer deaths in China. Immunotherapy has emerged as a promising treatment approach for advanced NSCLC without sensitive mutations. Sugemalimab, a fully human immunoglobulin G4 monoclonal antibody, retains its Fc function, inducing antibody-dependent cellular phagocytosis. This study aims to evaluate the real-world effectiveness and safety of Sugemalimab in various treatment patterns, particularly with radiotherapy, in Chinese NSCLC patients with locally advanced or metastatic disease. Methods: We retrospectively evaluated locally advanced (LA-) and metastatic (m-) NSCLC patients (pts) treated with Sugemalimab in Cancer Hospital, Chinese Academy of Medical Sciences from Feb. 2022 to Sep. 2023. Demographic characteristics, clinical features, genetic landscape and therapy patterns were collected. We employed descriptive statistics to determine the Objective Response Rate (ORR) and Disease Control Rate (DCR), and used the Kaplan-Meier method for estimating Progression-Free Survival (PFS) and Overall Survival (OS). Safety profiles, including adverse events and immune-related pneumonitis, were similarly analyzed. Results: 76 pts with LA-NSCLC and mNSCLC were enrolled. Majority were male (92.1%) and smokers (84.2%) and ECOG PS 0-1 (78.9%). Median age was 66. Squamous-cell carcinoma was found in 44 pts (57.9%). The main metastatic sites were bone, brain, liver, lung and lymph node for mNSCLC pts. Genetic profiling in 39 pts revealed TP53 mutations in 19 (48.7%) and KRAS mutations in 10 (25.6%). A total of 38 pts (51.3%) received 1L Sugemalimab therapy, while 21 pts (27.6%) receiving 2L. Main treatment pattern was Sugemalimab plus platinum-based chemo. Radiotherapy (RT) was main local therapy approach, concurrent with Sugemalimab in 18 pts. Majority of pts received either volumetric modulated arc therapy or intensity-modulated radiation therapy to thoracic lesions. Tomotherapy was administered to brain metastases in 2 pts. The median follow-up time was 9.18m at this cut-off date. 16 pts receiving Sugemalimab plus chemo achieved objective response (ORR 44.4%) and DCR was 91.5% in 1L therapy. Median PFS (mPFS) has not been reached. PFS rate at 6m, 12m was 75.6%, 62.1% respectively. 1L OS was immature. For pts receiving additional thoracic RT concurrent with 1L systematic therapy, mPFS was still not mature. PFS rate was 82.4% at 6m and 74.9% at 12 m. Common RT-related side effects were radiation pneumonitis, radiation esophagitis and skin injury. None immune-related pneumonitis was found in this population. Only one case of immune-related pneumonitis was observed in a pts without RT. Conclusions: Our study demonstrated Sugemalimab-based therapy provide clinical benefits to LA-NSCLC and mNSCLC with good safety in real-world setting. The combination treatment of Sugemalimab with radiotherapy illustrates low pulmonary toxicity and superior tolerability.

Integrated genomic and transcriptomic characterization of neuroendocrine carcinomas for improved treatment decision-making.

e15138 Background: Neuroendocrine carcinomas (NECs) are poorly characterized due to their innate heterogeneity, thus limiting treatment and clinical trial options for patients. Here, we used whole exome sequencing (WES) and RNA sequencing (RNA-seq) to explore the genetic and microenvironmental landscape of NECs in order to understand the unique features of different NEC types, with the aim of improving treatment modalities. Methods: We analyzed 51 NEC clinical samples morphologically verified by a pathologist: lung NEC (20 small cell NEC and 1 large cell NEC cases), gastroenteropancreatic NEC (GEP, 12 cases), cancer of unknown primary (7 cases), Merkel cell carcinoma (MCC, 5 cases), genitourinary tract NEC (3 cases), and breast NEC (3 cases). Findings on tumor mutational burden (TMB, mut/Mb), microsatellite instability (MSI), gene expression signatures, and tumor microenvironment (TME) profiling were reported. Small cell lung cancer (SCLC) subtyping was performed as reported by Gay et al. on the entire NEC cohort. Results: Half of the patients with lung NEC and 84% of those with extrapulmonary NEC satisfied the molecular inclusion criteria for clinical trials, with the most frequent criterion being KRAS G12X or G13X mutations. Among the extrapulmonary NEC samples, 13.7% were deemed eligible for targeted therapy, specifically for cases with BRAF V600E mutation and/or high TMB (&gt; 10 mut/Mb). We detected varying TMB and distinct gene expression features across the entire cohort. Specifically, we found 2 MCC cases to be Merkel cell polyomavirus-positive with low TMB and devoid of UV-associated mutations. One GEP-NEC case exhibited a high MSI (MSI-high) status. We detected 6 SCLC cases (3 non-smokers, 3 former smokers) with surprisingly low levels of tobacco-associated mutations (&lt;10% of all mutations). Two GEP-NEC cases had high levels of mutations associated with tobacco smoking. While TME profiling showed no significant difference in cell population makeup across all samples, transcriptional SCLC subtyping revealed significant differences among the cases. Inflammatory SCLC (SCLC-I) samples showed statistically significant enrichment of all subpopulations of the immune microenvironment (i.e., B cells, T cells, NK cells), supporting the use of immune checkpoint blockade for treatment. The POU2F3+ SCLC (SCLC-P) samples showed low expression of all neuroendocrine diagnostic markers (i.e., INSM1, NCAM1, SYP, CHGA). Conclusions: Given the heterogeneous molecular features across diverse NEC tumors, a uniform treatment strategy is unlikely to benefit all NEC patients. Hence, our ability to detect these unique molecular features is crucial for matching individual NEC patients with specific clinical trials and targeted therapies that may improve their outcomes. Thus, a concerted effort using in-depth genomic, transcriptomic, and TME profiling for NEC tumors is warranted.

Genetic landscape for majority and minority HIV-1 drug resistance mutations in antiretroviral therapy naive patients in Accra, Ghana

BackgroundThe successful detection of drug-resistance mutations (DRMs) in HIV-1 infected patients has improved the management of HIV infection. Next-generation sequencing (NGS) to detect low-frequency mutations is predicted to be useful for efficiently testing minority drug resistance mutations, which could contribute to virological failure. This study employed Sanger sequencing and NGS to detect and compare minority and majority drug resistance mutations in HIV-1 strains in treatment-naive patients from Ghana. MethodFrom a previous study, 20 antiretroviral therapy (ART)-naive participants were selected for a cross-sectional study. Sanger sequencing and NGS techniques were used to detect the majority and minority HIV drug resistance (HIVDR) mutations, respectively, in the protease (PR) and partial reverse transcriptase (RT) genes. NGS detected mutations at 1 % and 5 % frequencies and Sanger sequencing at ≥20 % frequencies. The sequences obtained from NGS and Sanger sequencing platforms were submitted to the Stanford HIV drug resistance database for subtyping, mutation identification, and interpretations. ResultsSequences from the twenty participants where the CRF02_AG was the predominant strain (16, 80 %) were analyzed. NGS detected 25 mutations in the RT and PR genes, compared to 21 mutations by Sanger sequencing. Minority DRMs were detected at the prevalence of 55.0 % with NGS against 35 % DRMs by Sanger sequencing. One of the patients had eight different HIVDR variants, with two minority variants. These mutations were directed against PI (K20I and D30DN), NNRTI (Y181C, M23LM and V108I) and NRTI (K65R, M184I, and D67N). ConclusionThe study affirms the usefulness of genomic sequencing for drug resistance testing in HIV. It further shows that Sanger sequencing alone may not be adequate to detect mutations and that NGS capacity should be developed and deployed in the Ghanaian clinical settings for patients living with HIV.

Genomic characteristics of tumour necrosis in lung squamous cell carcinoma.

e20030 Background: Tumor necrosis and cavity on enhanced chest CT are common hallmarks of lung squamous cell carcinoma (LUSC). However, the genetic characteristics of necrosis on CT scan remain unclear. This study aims to elucidate the genetic landscape of LUSC with tumor necrosis. Methods: We implemented transcriptome and whole-exome sequencing to analyze early postoperative LUSC specimens. They were classified into necrosis and non-necrosis group based on preoperative enhanced chest CT. Subsequently, the genomic landscape between the two groups were compared. To substantiate our findings, we further employed immunohistochemistry and analysis of a clinical cohort as comprehensive methods of validation. Results: In study cohort (65 samples), the necrosis group (n = 37) showed a higher number and length of copy number variations (CNVs) and elevated Genomic Instability Index (GII) compared to the non-necrosis group (n = 28). Transcriptome sequencing revealed increased hypoxic hallmarks and activation of 11 fundamental metabolic pathways in the necrosis group. Endothelial cells were observably fewer, but matrix remodeling score was higher in the necrosis group. Here, the decreased activity of several immune-related pathways, such as antigen processing and presentation, natural killer cell-mediated cytotoxicity, etc, were notably suppressed in the necrosis group. Immunohistochemistry indicated that the expressions of hypoxy-related genes (HIF-1, NDRG1), proliferation-related genes (ki-67) and angiogenesis related genes (CD31) in necrosis group were significantly higher than those in non-necrosis group. In the clinical validation cohort, we enrolled 538 advanced LUSC patients from 25 medical centers receiving systemic treatment, categorized into chemotherapy (n = 270) and ICIs (n = 268) groups. A notable difference in progression-free survival (PFS) was observed in the ICIs group, with patients without tumor necrosis or cavity exhibiting significantly longer PFS (8.7 vs. 6.5 months; HR 0.67; 95% CI 0.42–0.63; p &lt; 0.001). Multivariate Cox analysis identified necrosis or cavity as an independent predictor of reduced PFS (HR 0.68; 95% CI, 0.51-0.9; p = 0.007). Conclusions: LUSC with necrosis is distinguished by increased genomic instability, hypoxia, enhanced tumor proliferation, matrix remodeling, and an immunosuppressive tumor microenvironment. Baseline chest CT findings of tumor necrosis or cavities may serve as negative predictors for the efficacy of ICIs treatment in LUSC.

Joubert syndrome caused by a TMEM67 mutation: Genotype-phenotype analysis

Joubert syndrome (JS), a rare neurodevelopmental disorder, is characterized by a unique midbrain- hindbrain malformation known as the molar tooth sign, a distinctive radiological feature. Among the myriad manifestations associated with JS, the most prevalent features encompass hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been identified as contributors to the development of JS. This study aimed to pinpoint a pathogenic variant in JS within an Iranian consanguineous pedigree. We employed whole-exome sequencing (WES) to pinpoint a potential pathogenic variant likely responsible for the condition in an 8-year-old male patient. The WES analysis successfully revealed a novel homozygous missense mutation (c.725A&gt;T; p.Asn242Ile) within exon 8 (NM_153704.6) of the TMEM67 gene. Subsequent validation through Sanger sequencing confirmed the presence of the chr8-93780603A&gt;T mutation. This study elucidated JS within an Iranian family, uncovering a new TMEM67 gene mutation through comprehensive genetic analysis. The identification of this mutation enhances our understanding of the genetic landscape of JS, contributing valuable insights for both clinical diagnosis and future research endeavors.

Population genetic insights into the conservation of common walnut (Juglans regia) in Central Asia

The common walnut (Juglans regia) is one of the most economically important nut trees cultivated worldwide. Despite its importance, no comprehensive evaluation of walnut tree population genetics has been undertaken across the range where it originated, Central Asia. In this study, we investigated the genetic diversity and population structure of 1082 individuals from 46 populations across Central Asia. We found moderate genetic diversity of J. regia across Central Asia, with 46 populations clustered into three groups with a weak relationship between genetic and geographic distance. Our findings reveal that the western Himalaya might be the core region of common walnut genetic diversity in Central Asia and that, except for two populations in Gongliu Wild Walnut Valley, humans might have introduced walnut populations to Xinjiang, China. The observed distribution of the genetic landscape has probably been affected by historical climate fluctuation, breeding system, and prolonged anthropogenic activity. We propose the conservation of the core genetic diversity resources in the western Himalaya and pay special attention to populations from Gongliu in Xinjiang. These findings enhance our understanding of the genetic variation throughout the distribution range of J. regia in Central Asia, which will provide a key prerequisite for evidence-based conservation and management.

Genetic landscape of colorectal cancer (CRC) across genetic ancestries: Implications for early cancer detection (ECD).

e15527 Background: Blood-based ECD has the potential to reduce mortality rates by improving strategies for adoption of and adherence to screening. As health disparities in the incidence of CRC across minority populations are known to exist, we evaluated the genomic landscape in patients with CRC across genetic ancestries. Methods: De-identified patients (N = 16,337) with stage I-IV CRC had personalized, tumor-informed commercial ctDNA testing (SignateraTM) based on whole exome sequencing. Genetic ancestry determined via supervised local ancestry inference (pmid36042219) included African (AFR, n = 1697), Ashkenazi Jewish (ASJ, n = 1192), East Asian (EAS, n = 2247), European (EUR, n = 9726), Latino (LAT, n = 1291), and South Asian (SAS, n = 184) ancestries. Somatic driver mutations and pathogenic germline variants (PVs) in CRC-associated genes were evaluated. Somatic single nucleotide variants were used for mutational signature inference. Results: Across ancestries, 47-67% of the patients were male and most were aged &gt; 50 years. Among 35 to 50-year-olds, microsatellite instability (MSI) rates were higher in LAT (12.9%, p = 0.04) and SAS (28.3%, p &lt; 0.001) vs EUR (8.2%). Among &gt; 50-year-olds, MSI rates were lower in AFR (10.7%, p &lt; 0.001), EAS (7.9%, p &lt; 0.001), and LAT (10.4%, p &lt; 0.001) vs EUR (16.0%). The POLE signature was more common in AFR (2%, p = 0.001) vs EUR (1.1%). There were significant differences in the frequency of driver mutations and PV rates between non-EUR vs EUR ancestry groups (Table, *p &lt; 0.05, **p &lt; 0.001). Gene-level enrichment was observed in MLH1 for SAS (8.7%, p &lt; 0.001) and LAT (1.8%, p = 0.03), CHEK2 for AFR (0.4%, p = 0.03) and EAS (0.1%, p &lt; 0.001), and PMS2 (1.4%, p = 0.006) for AFR. Among patients aged ≤50 years, similar findings were observed, with differences driven by MSI rates and germline findings in Lynch syndrome (LS) genes. Conclusions: This is the first study to investigate genomic differences between multiple ancestry groups in the largest cohort to date, including EAS, LAT, and SAS populations. The differences observed between ancestries could provide insight into differences in both hereditary risk and subsequent tumor initiation and growth. Findings from this study may provide information for developing risk stratification and prevention strategies for the early detection of cancer and provide the rationale for precision treatment based on ancestry. [Table: see text]