Comparison Of Allele Frequencies Research Articles

The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients.

Since variants of uncertain significance (VUS) reported in genetic testing cannot be acted upon clinically, this classification may delay or prohibit precise diagnosis and genetic counseling in adult genetic disorders patients. Large-scale analyses about qualitatively distinct lines of evidence used for VUS can make them re-classification more accurately. We analyzed 458 Chinese adult patients WES data, within 15 pathogenic evidence PS1, PS2, PM1, PM6 and PP4 were not used for VUS pathogenic classification, meanwhile the PP3, BP4, PP2 were used much more frequently. The PM2_Supporting was used most widely for all reported variants. There were also 31 null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) which were probably the disease-causing variants of the patients were classified as VUS. By analyzed the evidence used for all VUS we recommend that appropriate genetic counseling, reliable releasing of in-house data, allele frequency comparison between case and control, expanded verification in patient family, co-segregation analysis and functional assays were urgent need to gather more evidence to reclassify VUS. We also found adult patients with nervous system disease were reported the most phenotype-associated VUS and the lower the phenotypic specificity, the more reported VUS. This result emphasized the importance of pretest genetic counseling which would make less reporting of VUS. Our result revealed the characteristics of the pathogenic classification evidence used for VUS in adult genetic disorders patients for the first time, recommend a rules-based process to evaluate the pathogenicity of VUS which could provide a strong basis for accurately evaluating the pathogenicity and clinical grade information of VUS. Meanwhile, we further expanded the genetic spectrum and improve the diagnostic rate of adult genetic disorders.

Vitamin D status and VDR gene polymorphisms in patients with growth hormone deficiency: A case control Tunisian study

IntroductionGrowth Hormone Deficiency (GHD) is a rare disease marked by a complete or partial reduction in the production of growth hormone. Vitamin D deficiency is frequent and may be associated with several pathologies. However, the association between GHD and vitamin D deficiency has not been extensively studied. This study aimed to analyse VDR gene polymorphisms related to vitamin D status to ensure better care for patients with GHD. Material and methodsA case-control study was conducted at the Children's Hospital of Tunis in collaboration with the Farhat Hached's Hospital of Sousse, including patients with GHD and healthy subjects. Genetic analysis of the VDR gene polymorphisms was performed using PCR-RFLP technique. Haplotypes were examined with Haploview software, while statistical analyses were carried out using SPSS and R programming language. ResultsOur study revealed significant differences in vitamin D (p = 0, 049) and calcium concentrations between patients and healthy subjects, which were lower in the GHD group (p = 0,018). A comparison of allelic and genotypic frequencies of the five polymorphisms indicated an association between the FokI polymorphism and GHD. Furthermore, significant difference was observed between the ApaI genotypes and PTH (p = 0,019) and ALP (p = 0,035). FokI genotypes were associated with phosphorus (p = 0,021). Additionally, One haplotype, CTAGT, exhibited a significant difference between the patients and healthy subjects (p = 0,002). ConclusionOur study findings indicate that hypovitaminosis D is common among patients with GHD, even when undergoing treatment with rhGH. This underscores the critical importance of vitamin D supplementation during treatment.

Mapping the Pharmacogenetic Landscape in a Ugandan Population: Implications for Personalized Medicine in an Underrepresented Population.

Africans are extremely underrepresented in global genomic research. African populations face high burdens of communicable and non-communicable diseases and experience widespread polypharmacy. As population-specific genetic studies are crucial to understanding unique genetic profiles and optimizing treatments to reduce medication-related complications in this diverse population, the present study aims to characterize the pharmacogenomics profile of a rural Ugandan population. We analyzed low-pass whole genome sequencing data from 1998 Ugandans to investigate 18 clinically actionable pharmacogenes in this population. We utilized PyPGx to identify star alleles (haplotype patterns) and compared allele frequencies across populations using the Pharmacogenomics Knowledgebase PharmGKB. Clinical interpretations of the identified alleles were conducted following established dosing guidelines. Over 99% of participants displayed actionable phenotypes across the 18 pharmacogenes, averaging 3.5 actionable genotypes per individual. Several variant alleles known to affect drug metabolism (i.e., CYP3A5*1, CYP2B6*9, CYP3A5*6, CYP2D6*17, CYP2D6*29, and TMPT*3C)-which are generally more prevalent in African individuals-were notably enriched in the Ugandan cohort, beyond reported frequencies in other African peoples. More than half of the cohort exhibited a predicted impaired drug response associated with CFTR, IFNL3, CYP2B6, and CYP2C19, and approximately 31% predicted altered CYP2D6 metabolism. Potentially impaired CYP2C9, SLCO1B1, TPMT, and DPYD metabolic phenotypes were also enriched in Ugandans compared with other African populations. Ugandans exhibit distinct allele profiles that could impact drug efficacy and safety. Our findings have important implications for pharmacogenomics in Uganda, particularly with respect to the treatment of prevalent communicable and non-communicable diseases, and they emphasize the potential of pharmacogenomics-guided therapies to optimize healthcare outcomes and precision medicine in Uganda.

HLA variants and their association with IgE-Mediated banana allergy: A cross-sectional study

BackgroundBanana allergy is on the rise in tropical regions. Advances in genomics and candidate gene identification have increased interest in genetic factors in food allergies. However, the genetic basis of IgE-mediated banana allergy is underexplored. ObjectiveTo characterize HLA variants and their association with IgE-mediated banana allergy. MethodsThis cross-sectional study recruited banana-allergic adults, confirmed by allergology tests, with non-allergic individuals as controls. Genomic DNA extraction and sequencing BAM files for HLA typing were conducted. Allele frequency was calculated using the direct counting method, and odds ratio (OR) with 95 % confidence interval (CI) were determined. Fisher's exact or chi-square tests were used to assess associations with Bonferroni's correction for multiple tests. The allele frequency of the Thai population from The Allele Frequency Net Database was used to compute the allele enrichment ratio (ER). ResultsA total of 59 cases and 64 controls were recruited. HLA genotyping indicated potential associations of HLA-B*15:25 (OR 11.872; p-value 0.027), HLA-C*04:03 (OR 7.636; p-value 0.033), and HLA-DQB1*06:09 (OR 11.558; p-value 0.039) with banana allergy. However, after Bonferroni correction, none of these associations reached statistical significance. Comparing allele frequency with the general population from The Allele Frequency Net Database, our ER analysis revealed a higher prevalence in the banana allergy group for B*15:25 (ER 1.849), C*04:03 (ER 1.332), and DQB1*06:09 (ER 6.602) alleles. ConclusionsThis study provides initial genetic insights into banana allergy, suggesting potential links with specific HLA alleles. Despite 12 initially identifying alleles, none were statistically significant after multiple testing correction. Larger studies are needed to detect possible significant correlations.

Supernatant fluid from endobronchial ultrasound-guided transbronchial needle aspiration for rapid next-generation sequencing

There is an increasing demand to optimize the workflow and maximize tissue available for next-generation sequencing (NGS) for non-small cell carcinoma. We looked at transbronchial needle endobronchial ultrasound-guided bronchoscopy with transbronchial needle aspiration samples and evaluated the performance of supernatant (SN) fluid processed from a dedicated aspirate collected for NGS testing. Nineteen samples were collected and processed using a new workflow. Five aspirates were collected in formalin. One additional dedicated pass was collected fresh and centrifuged. The resulting cell pellet was added to formalin for cell block (CB) processing. DNA and RNA were extracted from concentrated SN for targeted testing using the Oncomine Precision Assay (Thermo Scientific, Waltham, MA). NGS results from the corresponding CB samples were used as "controls" for comparison. Thirty-one mutations were detected in SN (Table1). The most frequently mutated genes were TP53 (35%), EGFR (23%), KRAS (13%), CTNNB1 (6%), and ERBB2 (6%). There was 100% concordance between the mutations detected in SN and corresponding CBs with comparable variant allele frequencies. Turnaround time of NGS results was 1 day for SN compared to 4-10 days for CB. We were able to demonstrate the usefulness of SN for reliable rapid molecular results. We successfully incorporated the workflow for tissue handling and processing among our clinical, cytopathology, and molecular teams. Molecular results were available at the same time as the cytologic diagnosis, allowing for timely reporting of a comprehensive diagnosis. This approach is particularly useful in patients with advanced disease requiring urgent management.

Characterization of the Common Genetic Variation in the Spanish Population of Navarre.

Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals of Spanish origin. Our analysis revealed 61,410 biallelic single nucleotide variants (SNV) within the Navarrese cohort, with 35% classified as common (MAF > 1%). By comparing allele frequency data from 1000 Genome Project (excluding the Iberian cohort of Spain, IBS), Genome Aggregation Database, and a Spanish cohort (including IBS individuals and data from Medical Genome Project), we identified 1069 SNVs common in Navarre but rare (MAF ≤ 1%) in all other populations. We further corroborated this observation with a second regional cohort of 239 unrelated exomes, which confirmed 676 of the 1069 SNVs as common in Navarre. In conclusion, this study highlights the importance of population-specific characterization of genetic variation to improve allele frequency filtering in sequencing data analysis to identify disease-causing variants.

Genomic susceptibility to gastric cancer in Northwest Iran: population-based and case–control studies

IntroductionThe age-standardized incidence rate for gastric cancer is estimated to be 11.1% worldwide and 39.1% for Ardabil province in northwest Iran. Single nucleotide polymorphisms (SNPs) occur in coding and non-coding regions, contributing to cancer susceptibility. To identify SNPs predisposing individuals to gastric cancer in this region, we compared 263 variants between the Ardabil population and other populations.Materials and methodsWhole exome sequencing was used to determine the distribution of variants in the genomic DNA of 150 volunteers (aged < 35 years) from the general population of Ardabil. We compared allele frequencies with databases such as Iranome, Alfa, GnomAD, and 1000G, and statistically analyzed their correlation with age-standardized incidence rates (ASRs) for gastric cancer in related populations using the Pearson correlation test. Some findings were validated using Sanger-based PCR-Sequencing. We determined the frequency of seventeen variants among 150 individuals with gastric cancer and 150 healthy volunteers (matched for age and sex) as the control group.ResultsNineteen variants, including rs10061133, rs1050631, rs12220909, rs12983273, rs1695, rs2274223, rs2292832, rs2294008, rs2505901, rs2976391, rs33927012, rs3744037, rs3745469, rs4789936, rs4986790, rs4986791, rs6194, rs63750447, and rs6505162, were found to be significantly different between the general population of Ardabil and other populations. Among them, the variants rs1050631, rs12983273, rs1695, rs2274223, rs2292832, rs2505901, rs33927012, rs374569, and rs6505162 showed significant differences between the cases and controls.DiscussionIn this study, 17 variants appeared to be involved in the etiology of the high frequency of gastric cancer in the Ardabil population. Some of the observed differences were consistent with previous case–control and meta-analysis reports from various parts of the world. These findings motivate further cohort investigations in this population. Ultimately, identifying prognostic factors can help diagnose individuals predisposed to gastric cancer in this population.

Abstract 5686: Identifying rare microRNA risk variants for hereditary breast cancer in African American individuals

Abstract Background: In the United States, breast cancer is the most frequently diagnosed cancer in women. However, African American women tend to have a higher incidence of triple negative breast cancer cases, and an earlier age of disease onset, which are hallmark characteristics of heredity disease. Even with current breakthroughs in breast cancer research, limited research participation from women of African descent has led to a gap in our knowledge of heredity factors that are involved in disease in this population. Furthermore, most breast cancer research has focused on protein coding genes being the culprit of tumorigenesis; however, within the last three decades, research efforts have begun to focus on noncoding RNAs, like microRNAs (miRNAs), as potential factors to promote carcinogenesis. miRNAs are short, noncoding RNA molecules that control gene expression at the post-translational level. miRNAs have several mechanisms to affect gene expression of cellular processes like cell proliferation, apoptosis, invasion, and metastasis. However, the identification and functional role miRNA risk variants play in African American breast cancer is still not fully understood. Methods: 30X whole genome sequencing (WGS) was carried out on an Illumina platform on blood- or saliva-derived DNA from 120 African American breast cancer cases from the Alabama Hereditary Cancer Cohort. The WGS data was analyzed using our established bioinformatics pipeline, which has been adapted from the Genome Analysis Toolkit (GATK) Best Practice Pipeline. Focusing on miRNA variants as risk factors, a miRNA BED file was used to extract regions harboring miRNA genes. The resulting file was then filtered for rare miRNA variants (minor allele frequency &amp;lt;1%) in the African American population based on the Genome Aggregation Database (gnomAD) allele frequency. P-values for variants of interest were calculated using Fisher’s Exact tests. Results: Sequencing data have revealed three rare miRNA variants from our African American cohort that can be potentially associated with breast cancer risk. Upon statistical analysis comparing allele frequencies between the African American general population and the Alabama Hereditary Cancer Cohort, miR7850, miR3145, and miR8074 had p-values 5.21E-05, 3.58E-05, and 2.19E-04, respectively. Conclusions: We have identified three rare miRNA variants that were not previously known to be associated with breast cancer risk. Interestingly, both miR7850 and miR8074 target TP53 and miR3145 targets GREM1 and PALB2, which these targets are known breast cancer susceptibility genes. Understanding the consequence of these variants is important to add to our knowledge of miRNAs that play critical roles in carcinogenesis leading to better treatment strategies. Citation Format: Sheniqua R. Glover, Troy LoBue, Nancy D. Merner. Identifying rare microRNA risk variants for hereditary breast cancer in African American individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5686.

Genome-wide analysis of spina bifida risk variants in a case-control study from Bangladesh.

Human studies of genetic risk factors for neural tube defects, severe birth defects associated with long-term health consequences in surviving children, have predominantly been restricted to a subset of candidate genes in specific biological pathways including folate metabolism. In this study, we investigated the association of genetic variants spanning the genome with risk of spina bifida (i.e., myelomeningocele and meningocele) in a subset of families enrolled from December 2016 through December 2022 in a case-control study in Bangladesh, a population often underrepresented in genetic studies. Saliva DNA samples were analyzed using the Illumina Global Screening Array. We performed genetic association analyses to compare allele frequencies between 112 case and 121 control children, 272 mothers, and 128 trios. In the transmission disequilibrium test analyses with trios only, we identified three novel exonic spina bifida risk loci, including rs140199800 (SULT1C2, p = 1.9 × 10-7), rs45580033 (ASB2, p = 4.2 × 10-10), and rs75426652 (LHPP, p = 7.2 × 10-14), after adjusting for multiple hypothesis testing. Association analyses comparing cases and controls, as well as models that included their mothers, did not identify genome-wide significant variants. This study identified three novel single nucleotide polymorphisms involved in biological pathways not previously associated with neural tube defects. The study warrants replication in larger groups to validate findings and to inform targeted prevention strategies.

The Case for Pre-Emptive Pharmacogenetic Screening in South Africa.

Lack of equitable representation of global genetic diversity has hampered the implementation of genomic medicine in under-represented populations, including those on the African continent. Data from the multi-national Pre-emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study suggest that genotype guidance for prescriptions reduced the incidence of clinically relevant adverse drug reactions (ADRs) by 30%. In this study, hospital dispensary trends from a tertiary South African (SA) hospital (Steve Biko Academic Hospital; SBAH) were compared with the drugs monitored in the PREPARE study. Dispensary data on 29 drugs from the PREPARE study accounted for ~10% of total prescriptions and ~9% of the total expenditure at SBAH. VigiLyze data from the South African Health Products Regulatory Authority were interrogated for local ADRs related to these drugs; 27 were listed as being suspected, concomitant, or interacting in ADR reports. Furthermore, a comparison of pharmacogene allele frequencies between African and European populations was used to frame the potential impact of pre-emptive pharmacogenetic screening in SA. Enumerating the benefit of pre-emptive pharmacogenetic screening in SA will only be possible once we initiate its full application. However, regional genomic diversity, disease burden, and first-line treatment options could be harnessed to target stratified PGx today.

An intermediate-sized donor registry experience: HLA barriers in matching procedures.

The data enabling the estimation of the possibility of finding a matched unrelated donor (MUD) within a relatively short time is important for the success of hematopoietic stem cell transplantation (HSCT). In the present study, 738 unrelated Croatian patients in the program of unrelated HSCT were retrospectively analyzed for gender matching, donor origin (national or international), the distribution of HLA alleles and haplotypes, as well as for the probability of finding a 9-10/10 MUD. Almost 70% of the patients in our study group had a 10/10 MUD, while among the patients with a 9/10 MUD, a 1st field resolution level mismatched donor was selected for 55.0% of patients. The majority of pairs were HLA-A mismatched (33.8%). A comparison of HLA allele frequencies between two subgroups of patients revealed significant differences for 13 alleles. However, after p value correction, the difference in frequency remained significant only for four alleles; three HLA alleles (B*08:01, C*07:01, and DRB1*03:01) demonstrated a significantly higher frequency among patients with a 10/10 MUD (Pcorr < 0.0001, Pcorr = 0.0096, and Pcorr < 0.0001, respectively), while the B*35:08 allele was significantly more present among patients with a 9/10 MUD (Pcorr = 0.0328). The comparison of the distribution of HLA haplotypes between patients with a 10/10 MUD and patients with a 9/10 MUD showed significant differences for a number of two-locus and three-locus haplotypes, as well as for one five-locus haplotype (HLA-A*01:01~B*08:01~C*07:01~DRB1*03:01~DQB1*02:01), which was significantly more present in the group of patients with a 10/10 MUD. At least one HLA haplotype from the group of non-frequent HLA haplotypes (positions >1000) was carried by patients with a 9/10 MUD. The data obtained by the present study will contribute to a better estimation of the probability of finding a suitable 9-10/10 MUD for Croatian patients in need of HSCT.

Comparison of Allele Frequencies of Benghazi Population with Other Metapopulation

This is, to our knowledge, the first in-depth and largest study (238 samples) of genetic diversity in Y-STR haplotypes in an eastern Libyan population (recorded in Afro-Asiatic group from Metapopulation published in Y-STR Haplotype Reference Database-YHRD). Two previous studies, of a Tripoli population (West of Libya) and a Fezzan population (South Libya) analyzed a smaller number of inhabitants (63 samples and 47 samples, respectively) and (YHRD). Recently, (April 2011) YHRD recorded 47 and 82 haplotypes from Tripoli (Berber and Arabs 2011) respectively. Method: We Compare allele frequencies of Benghazi population with Y-STR Haplotype Reference Database -metapopulation. Conclusion: Benghazi population is similar to other Asian groups, such as Euro-Asian and East Asian. Hence, the Benghazi population shows genetic affinity to Asian and Middle Eastern rather than African and West North African groups.

Characterization of CYP2B6 and CYP2A6 Pharmacogenetic Variation in Sub-Saharan African Populations.

Genetic variation in CYP2B6 and CYP2A6 is known to impact interindividual response to antiretrovirals, nicotine, and bupropion, among other drugs. However, the full catalogue of clinically relevant pharmacogenetic variants in these genes is yet to be established, especially across African populations. This study therefore aimed to characterize the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy, and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n = 2,000). This study presents frequency information for star alleles in CYP2B6 (e.g., *6 and *18; frequency of 21-47% and 2-19%, respectively) and CYP2A6 (e.g., *4, *9, and *17; frequency of 0-6%, 3-10%, and 6-20%, respectively), and predicted phenotypes (for CYP2B6), across various African populations. In addition, 50 potentially novel African-ancestry star alleles were computationally predicted by StellarPGx in CYP2B6 and CYP2A6 combined. For each of these genes, over 4% of the study participants had predicted novel star alleles. Three novel star alleles in CYP2A6 (*54, *55, and *56) and CYP2B6 apiece, and several suballeles were further validated via targeted Single-Molecule Real-Time resequencing. Our findings are important for informing the design of comprehensive pharmacogenetic testing platforms, and are highly relevant for personalized medicine strategies, especially relating to antiretroviral medication and smoking cessation treatment in Africa and the African diaspora. More broadly, this study highlights the importance of sampling diverse African ethnolinguistic groups for accurate characterization of the pharmacogene variation landscape across the continent.

Examination of Genetic Risk Factors for Alzheimer’s Disease in a Cohort of Familial Longevity: the Long Life Family Study

AbstractBackgroundGenetic risk factors have been explored extensively for late onset Alzheimer’s Disease (LOAD). The largest meta‐analysis GWAS studies to date (Bellenguez et al., 2022) identified 83 single nucleotide polymorphisms (SNPs) associated with LOAD in the general population. The Long Life Family Study (LLFS) is aimed to identify factors associated with familial longevity and healthy aging by examining US and Danish families. Our earlier studies have shown that LLFS families are at lower risk of several age‐related diseases, including LOAD. Here, we will: (1) compare allele frequencies and effect sizes of the identified meta‐GWAS variants against those in LLFS; and (2) assess whether a polygenic risk score (PRS) based on meta‐GWAS variants differs between LOAD vs. cognitively healthy in LLFS.MethodWe examined LLFS participants who were Non‐Hispanic Whites, had available cognitive and whole genome sequencing (WGS) (n = 4,220). Allele frequencies were estimated based on founders only. Association analyses were performed via logistic regression using Wald test and adjusting for sex, age, site, education, first principal components, and the genetic relationship matrix. PRS was calculated using a weighted formula, and to account for family structure, means for each status per family were obtained.ResultIndependent of LOAD status, 13 SNPs had significantly different allele frequencies between the two studies. Minor allele frequencies of 10 of the SNPs were lower in LLFS when compared with Bellenguez et al. When examining the relations between LOAD and the 77 available SNPs, only five variants appeared to be associated in LLFS. The direction of association differed for two of the SNPs. Lastly, estimated PRS scores did not differ by LOAD status (affected vs unaffected: ‐0.059 vs. ‐0.054, respectively).ConclusionHere we show that variants associated with LOAD in the general population were not necessarily associated with LOAD in in the LLFS cohort, a cohort ascertained for familial healthy aging. When estimating disease risk using genetic markers, as expected, ascertainment needs to be taken into consideration.

Problems with studying directional natural selection in humans.

The review describes the main methods for assessing directional selection in human populations. These include bioinformatic analysis of DNA sequences via detection of linkage disequilibrium and of deviations from the random distribution of frequencies of genetic variants, demographic and anthropometric studies based on a search for a correlation between fertility and phenotypic traits, genome-wide association studies on fertility along with genetic loci and polygenic risk scores, and a comparison of allele frequencies between generations (in modern samples and in those obtained from burials). Each approach has its limitations and is applicable to different periods in the evolution of Homo sapiens. The main source of error in such studies is thought to be sample stratification, the small number of studies on nonwhite populations, the impossibility of a complete comparison of the associations found and functionally significant causative variants, and the difficulty with taking into account all nongenetic determinants of fertility in contemporary populations. The results obtained by various methods indicate that the direction of human adaptation to new food products has not changed during evolution since the Neolithic; many variants of immunity genes associated with inflammatory and autoimmune diseases in modern populations have undergone positive selection over the past 2-3 thousand years owing to the spread of bacterial and viral infections. For some genetic variants and polygenic traits, an alteration of the direction of natural selection in Europe has been documented, e. g., for those associated with an immune response and cognitive abilities. Examination of the correlation between fertility and educational attainment yields conflicting results. In modern populations, to a greater extent than previously, there is selection for variants of genes responsible for social adaptation and behavioral phenotypes. In particular, several articles have shown a positive correlation of fertility with polygenic risk scores of attention deficit/hyperactivity disorder.

Characterization of Cases with the Rare Cytogenetic Abnormality I(7)(p10) Reveals an Association with IDH2 Mutated Acute Myeloid Leukemia

Background: The chromosomal alteration i(7)(p10) is a rare abnormality in hematological malignancies. It leads to a loss of the long arm (7q) and duplication of the short arm (7p) of chromosome 7. However, the presence, frequency and clinical implications of i(7)(p10) in hematological neoplasms has not been analyzed systematically to date. Aim: (1) Analysis of the frequencyand occurrence of i(7)(p10) in hematological malignancies. (2) Characterization of additional cytogenetic alterations and co-occurring mutations. (3) Analysis of potential clinical implications. Patients and methods: All samples sent for diagnosis of suspected hematologic neoplasms between 08/2005 - 05/2023 were used for detection of i(7)(p10). Presence of i(7)(p10) was analyzed using chromosome banding analysis (CBA). In cases with available molecular genetic analyses the following genes were analyzed: ASXL1, BCOR, CEBPA, DNMT3A, EZH2, FLT3-ITD, IDH1, IDH2, KRAS, NPM1, NRAS, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1 and ZRSR2. Variants of unknown significance were excluded from statistical analysis. All reported p-values are two-sided and were considered significant at p&amp;lt;0.05. Results: In 34 cases an i(7)(p10) was detected. Regarding specific entities, i(7)(p10) was mainly found in AML (23/34, 68%) and rarely in other entities (mature B-cell neoplasms (B-NHL): 6/34, 18%; MDS: 4/34, 12%; ALL: 1/34, 3%). In 20/34 cases, i(7)(p10) comprised the sole cytogenetic abnormality, including 19 AML cases and 1 MDS case. In 10/34 cases, additional chromosomal alterations were detected, leading to a complex karyotype in 5 of these cases. Of note, all cases with a complex karyotype were B-NHL. Additionally, in 4 cases i(7)(p10) was present only in a subclone (1 AML, 1 B-NHL, 2 MDS cases) (Figure A). In 18/34 cases, molecular genetic data was available, revealing DNMT3A (15/18), IDH2 (14/18) and BCOR (7/18) as most frequently mutated genes. As these 18 cases comprised n=15 cases diagnosed as AML, further analysis focused on these patients only. 14/15 cases harbored a mutation in IDH2, the remaining case showed an IDH1 mutation. Further, in 14/15, 7/15 and 4/15 cases, mutations in DNMT3A, BCOR and EZH2 were detected, respectively. By contrast, mutations that are known to frequently co-occur with IDH2 mutations in AML ( SRSF2, ASXL1, NPM1, STAG2, RUNX1, NRAS) were absent or only very rarely detected (Figure B). 12/14 cases with IDH2 mutations showed the mutation site p.Arg172Lys, 2/14 cases p.Arg140Leu, which is known to be the most frequent IDH2 mutation site. This is corroborated by analysis of a control cohort of n=60 IDH2 mutated AML cases without i(7)(p10), in which only 8/60 cases with p.Arg172Lys were detected (86% vs. 13%, p&amp;lt;0.001). Further, comparison of variant allele frequency (VAF) of IDH2 with the VAF of co-mutations suggested the presence of IDH2 in the main clone of all cases, although IDH2 VAF of cases with i(7)(p10) was slightly but not significantly lower than the IDH2 VAF of AML cases without i(7)(p10) (38.3 vs. 45.9). Moreover, comparison of IDH2 mutated AML with and without i(7)(p10) revealed a predominance of females (13/14, 93% vs. 29/60, 48%, p&amp;lt;0.001) and of younger age (63 vs. 72 years, p=0.015) in cases with i(7)(p10). Analysis of overall survival (OS) did not reveal a significant difference between IDH2 mutated AML cases with and without i(7)(p10), although cases with i(7)(p10) showed a trend towards a better outcome (37 vs. 14 months). Conclusions: (1) The rare but recurrent cytogenetic aberration i(7)(p10) is mainly found in AML, where associations with mutations in IDH2, DNMT3A and BCOR were observed. By contrast, other AML-defining mutations ( NPM1, FLT3-ITD, CEPBA) were largely absent, further no defining fusions/rearrangements or a complex karyotype were detected. (2) The vast majority of patients were female and younger than patients with IDH2 mutation without i(7)(p10). (3) Almost all cases showed the rare hotspot p.Arg172Lys and i(7)(p10) as sole aberration, thus it can be speculated that these cases define a distinct subgroup. (4) OS seems to be slightly better than in IDH2 mutated AML without i(7)(p10), although this difference was not statistically significant. (5) Taking into account that the IDH2 mutation was always detected in the main clone and that no other targetable genes/aberrations were observed, these patients are potentially suitable for targeted therapy with IDH inhibitors.

Role of miRNA Let-7 in Plasma of Rheumatoid Arthritis.

Objectives: Micro ribonucleic acids (miRNAs) are noncoding RNAs, recently implicated as potential biomarkers or therapeutic targets for autoimmune diseases such as rheumatoid arthritis (RA). The aim of this study is to assess the role of miRNA Let-7 in the plasma of RA. Materials and methods: Trained medical staff already enrolled for the study collected blood samples from healthy controls (N = 42) and RA patients (N = 44). In the laboratory, these samples were centrifuged at 2000 rpm for 8 minutes to separate serum from the sample, which was then transferred to a plain vial. Until transport to the genetic lab, samples were stored at -20°C Deoxyribonucleic acid (DNA) was isolated using a standard protocol cohort of controls and patient blood samples. Quantification of DNA was conducted using ultraviolet (UV) spectroscopy, and DNA quality was assessed on 0.8% agarose gel. A comparison of genotype frequencies in the different study groups was performed using the Chi-squared test, while a comparison of allelic frequencies was conducted using Fisher's exact test. Results: Variations of alleles, such as 16539423 (G>T), 16539433 (T>G), and 16539629 (A>T) were found only in RA patients. On the other hand, 16539617 (T>A), 16539622 (G>T), and 16539624 (T>C) were found only in control cases. Five sequences (three RA variants and two control variants) with minimal alignment were compared to the wild-type sequence. We found that the sequence modification of pre-miRNA 16539623 del G was significantly higher and had a risk allele in the study group [odds ratio (OR) = 3.29]. Conclusion: Rheumatoid arthritis (RA) is an autoimmune disorder that presents with a variety of clinical manifestations. Genetic factors possibly account for about 60% of disease susceptibility and expression, thus playing a very important role in disease pathogenesis. How to cite this article: Gauri LA, Liyakat N, Dadhich D, et al. Role of miRNA Let-7 in Plasma of Rheumatoid Arthritis. J Assoc Physicians India 2023;71(11):50-52.

The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

Functional analysis of CTLA4 promoter variant and its possible implication in colorectal cancer immunotherapy.

Colorectal cancer (CRC) is a prevalent cancer, ranking as the third most common. Recent advances in our understanding of the molecular causes of this disease have highlighted the crucial role of tumor immune evasion in its initiation and progression. CTLA4, a receptor that acts as a negative regulator of T cell responses, plays a pivotal role in this process, and genetic variations in CTLA4 have been linked to CRC susceptibility, prognosis, and response to therapy. We conducted a case-control study involving 98 CRC patients and 424 controls. We genotyped the CTLA4 c.-319C > T variant (rs5742909) and performed an association analysis by comparing allele frequencies between the patients and controls. To assess the potential functional impact of this variant, we first performed an In Silico analysis of transcription factor binding sites using Genomatix. Finally, to validate our findings, we conducted a luciferase reporter gene assay using different cell lines and an electrophoretic mobility shift assay (EMSA). The case-control association analysis revealed a significant association between CTLA4 c.-319C > T and CRC susceptibility (p = 0.023; OR 1.89; 95% CI = 1.11-3.23). Genomatix analysis identified LEF1 and TCF7 transcription factors as specific binders to CTLA4 c.-319C. The reporter gene assay demonstrated notable differences in luciferase activity between the c.-319 C and T alleles in COS-7, HCT116, and Jurkat cell lines. EMSA analysis showed differences in TCF7 interaction with the CTLA4 C and T alleles. CTLA4 c.-319C > T is associated with CRC susceptibility. Based on our functional validation results, we proposed that CTLA4 c.-319C > T alters gene expression at the transcriptional level, triggering a stronger negative regulation of T-cells and immune tumoral evasion.

Studying the genetics of participation using footprints left on the ascertained genotypes.

The trait of participating in a genetic study probably has a genetic component. Identifying this component is difficult as we cannot compare genetic information of participants with nonparticipants directly, the latter being unavailable. Here, we show that alleles that are more common in participants than nonparticipants would be further enriched in genetic segments shared by two related participants. Genome-wide analysis was performed by comparing allele frequencies in shared and not-shared genetic segments of first-degree relative pairs of the UK Biobank. In nonoverlapping samples, a polygenic score constructed from that analysis is significantly associated with educational attainment, body mass index and being invited to a dietary study. The estimated correlation between the genetic components underlying participation in UK Biobank and educational attainment is estimated to be 36.6%-substantial but far from total. Taking participation behaviour into account would improve the analyses of the study data, including those of health traits.