Minor allele frequency of myeloproliferative neoplasm mutations in the Irish blood donor population

2015 ◽  
Vol 34 (3) ◽  
pp. 161-164
Author(s):  
Glen J. Titmarsh ◽  
Gareth J. McKay ◽  
Mark Lawler ◽  
Lesley A. Anderson ◽  
Mary Frances McMullin
Keyword(s):  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Blood Donor ◽  
Myeloproliferative Neoplasm ◽  
Minor Allele ◽  
Donor Population

P–541 Identification of novel variants and candidate genes in women with familial idiopathic premature ovarian failure using whole-exome sequencing

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
R Morale. Sabater ◽  
B Lledo ◽  
J A Ortiz ◽  
F Lozano ◽  
A Bernabeu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Allele Frequency ◽  
Whole Exome Sequencing ◽  
Minor Allele Frequency ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Failure ◽  
Minor Allele ◽  
Whole Exome

Abstract Study question Is it possible to identify a genetic cause of familial premature ovarian failure (POF) with whole-exome sequencing (WES)? Summary answer Whole-exome sequencing is the most efficient strategy to identify probably pathogenic mutations in different genes in pathologies of polygenic etiology such as premature ovarian failure. What is known already Premature ovarian failure is the loss of ovarian function before the age of 40, and it is a common cause of infertility in women. This pathology has a heterogeneous etiology. Some chromosomal and genetic alterations have been described, and could explain approximately 20% of cases. However, in most patients the origin remains unknown. Recent studies with next-generation sequencing (NGS) have identified new variants in candidate genes related with premature ovarian insufficiency (POI) or premature ovarian failure (POF). These genes are not only involved in processes such as folliculogenesis, but also with DNA damage repair, homologous recombination, and meiosis. Study design, size, duration Fourteen women, from 7 families, affected by idiopathic POF were included in the study from October 2019 to September 2020. Seven POF patients were recruited when they came to our clinic to undergo assisted reproductive treatment. In the anamnesis, it was found that they had relatives with a diagnosis of POF, who were also recruited for the study. The inclusion criteria were amenorrhea before 38 years old and analytical and ultrasound signs of ovarian failure. Participants/materials, setting, methods WES was performed using TrusightOne (Illumina®). Sequenced data were aligned through BWA tool and GATK algorithm was used for SNVs/InDel identification. VCF files were annotated using Variant Interpreter software. Only the variants shared by each family were extracted for analysis and these criteria were followed: (1) Exonic/splicing variants in genes related with POF or involved in biological ovarian functions (2) Variants with minor allele frequency (MAF) ≤0.05 and (3) having potentially moderate/strong functional effects. Main results and the role of chance Seventy-nine variants possibly related with the POF phenotype were identified in the seven families. All these variants had a minor allele frequency (MAF) ≤0.05 in the gnomAD database and 1000 genomes project. Among these candidate variants, two were nonsense, six splice region, one frameshift, two inframe deletion and 68 missense. Thirty-two of the missense variants were predicted to have deleterious effects by minimum two of the four in silico algorithms used (SIFT, PolyPhen–2, MutationTaster and PROVEAN). All variants were heterozygous, and all the families carried three or more candidate variants. Altogether, 43 probably damaging genetic variants were identified in 39 genes expressed in the ovary and related with POF/POI or linked to ovarian physiology. We have described genes that have never been associated to POF pathology, however they may be involved in key biological processes for ovarian function. Moreover, some of these genes were found in two families, for example DDX11, VWF, PIWIL3 and HSD3B1. DDX11 may function at the interface of replication-coupled DNA repair and sister chromatid cohesion. VWF gene is suggested to be associated with follicular atresia in previous studies. PIWIL3 functions in development and maintenance of germline stem cells, and HSD3B1 is implicated in ovarian steroidogenesis. Limitations, reasons for caution Whole-exome sequencing has some limitations: does not cover noncoding regions of the genome, it also cannot detect large rearrangements, copy-number variants (large deletions/duplications), mosaic mutations, mutations in repetitive or high GC rich regions and mutations in genes with corresponding pseudogenes or other highly homologous sequences. Wider implications of the findings: WES has previously shown to be an efficient tool to identify genes as cause of POF, and has demonstrated the polygenic etiology. Although some studies have focused on it, and many genes are identified, this study proposes new candidate genes and variants, having potentially moderate/strong functional effects, associated with POF. Trial registration number Not applicable

MO275RARE VARIANTS OF COMPLEMENT FACTOR H AND THROMBOMODULIN ARE OVER-REPRESENTED IN A COHORT OF SEVERE IGA NEPHROPATHY PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Nicolas Maillard ◽  
Veronique Fremeaux Bacchi ◽  
Paula Vieira-Martins ◽  
Perrine Jullien ◽  
Eric Alamartine ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Allele Frequency ◽  
Rare Variant ◽  
Minor Allele Frequency ◽  
Rare Variants ◽  
Regulatory Genes ◽  
Factor H ◽  
Minor Allele ◽  
Risk Haplotype ◽  
Complement Factor

Abstract Background and Aims IgA nephropathy is the most frequent primary glomerulonephritis leading to end stage renal disease (ESRD) in about 30% of cases within 20 years after diagnosis. Complement activation through alternative and lectin pathways has been described to impact the pathogeny of the disease. We hypothesized in this study that rare variants of alternative pathways regulatory genes could be overrepresented and could play a role at initiating the disease and could harm the prognosis of IgA Nephropathy. Method Patients with biopsy proven IgA nephropathy with markers of severity comprising an evolution through ESRD and/or a proteinuria >0.5g/day with available DNA sample were included. All coding sequences of CFH, CFI, MCP, C3, Factor B THBD and CFHR5 genes were analyzed by next generation sequencing. We defined a variant as rare when its minor allele frequency was below 0.1% in the general population. Frequencies were compared to a French volonteers cohort (n=80) and a European large cohort (n=503) Results We screened 128 patients with IgA N, with following characteristics at diagnosis: median age 42.4 yo, proteinuria (median) 1.4g/day, hypertension 66%, median eGFR 48.7 mL/min/1.73m². The median follow-up was 99 months and 58% of patients progressed to ESRD. We identified rare variants with MAF<0.1% in 10.2 % (n=13) including 1 patient with two rare variants. The functional consequences of the 12 out the 14 variants are unknown. Two variants in CFH are located in function domains and are pathogenic. Patients with IgA N have high rates of rare variants in CFH (n=9/128 ; 7 %) versus normal controls (n=9/503 ; 1.8%) (p=0.004); Pathogenic Variants with minor allele frequency <0.1% in CFH were found in 2 IgA N (2 out of 128, 1.5%) versus 1 European controls (1 out of 503) In total, 11 % (14/128), 3.8 % (5/128) and 0.8 % (1/128) of the 128 patients were homozygous for the at-risk haplotype MCP ggaac, CFH tgtgt or both, respectively (versus 6.2 % (5/80), 3.8 % (3/80) and 0% in the controls) 6 patients carried the pathogenic variant in THDM gene p.Ala43Thr (6/128) versus 5 in 508 controls population (p=0.01). No difference in term of hypertension, proteinuria, eGFR, Oxford classification, vascular score at diagnosis was noticed between patients without any rare variant compared to patients with at least one rare variant. The progression through ESRD was not different between groups. Conclusion In this cohort of Caucasian IgA nephropathy patients, rare variants of CFH and THBD were found significantly overrepresented compared to a French and European control cohort. Rare variants of alternative pathway regulatory genes were not associated with particular severity or prognosis.

Abstract 468: Previously Unrecognized Intronic Variants in the Dystrophin Gene Identified as Possible Contributors to Dilated Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Alex Gyftopoulos ◽  
Tamara Ashvetiya ◽  
Yi-Ju Chen ◽  
Libin Wang ◽  
Charles H Williams ◽  
...  
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Mixed Model ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Minor Allele ◽  
Intronic Variants

Nonischemic dilated cardiomyopathy (DCM) often has a genetic etiology, however, its prevalence and etiologies are not completely understood. The UK Biobank comprises clinical and genetic data for greater than 500,000 individuals with enrollees 40-69 years of age. Our group created a custom phenotype of heart failure using ICD-10 codes for several subtypes of heart failure diagnoses including DCM. We then compared the individuals included in the custom heart failure phenotype to control individuals in a 20-to-1 fashion to identify genetic differences. Data were compared using Mixed Model Analysis for Pedigrees/Populations (MMAP) mixed-model regression. We identified 8 unlinked intronic variants in the dystrophin gene ( DMD ) that, when separated by self-identified race, occurred with a combined minor allele frequency of 0.15 in individuals with heart failure who identified as being of African descent. The combined minor allele frequency of these variants was 0.05 in individuals who self-identified as being of European descent. One variant of DMD in particular (rs139029250), was identified with a minor allele frequency of 0.05 in African British with DCM. The unadjusted odds ratio of a diagnosis of heart failure in individuals with rs129029250 was 4.65. When separated by gender, the unadjusted odds ratios are 2.02 for females and 6.44 for males. DMD is most notably known for its role in Duchenne and Becker muscular dystrophy, both of which are known to cause dilated cardiomyopathy in affected individuals. However, none of the individuals (36 female and 43 male) identified in our analysis with rs129029250 have been diagnosed with Duchenne muscular dystrophy, Becker muscular dystrophy, or a primary disorder of muscle (ICD code G70). Additionally, these individuals have an intronic variant of DMD , while Duchene and Becker muscular dystrophy are both due to exonic mutations. These findings suggest a possible common variant in the DMD gene that may contribute to DCM in individuals of African descent.

Mutation profile of over 4500 SARS-CoV-2 isolations reveals prevalent cytosine-to-uridine deamination on viral RNAs

2020 ◽  
Vol 15 (14) ◽  
pp. 1343-1352
Author(s):  
Yue Li ◽  
Xinai Yang ◽  
Na Wang ◽  
Haiyan Wang ◽  
Bin Yin ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Point Mutation ◽  
Minor Allele Frequency ◽  
Point Mutations ◽  
Minor Allele ◽  
Unique Point ◽  
Random Mutation ◽  
Viral Rnas ◽  
Mutation Profile ◽  
Mutation Type

Aim: The inference of coronavirus evolution is largely based on mutations in SARS-CoV-2 genome. Misinterpretation of these mutations would mislead people about the evolution of SARS-CoV-2. Materials & methods: With 4521 lines of SARS-CoV-2, we obtained 3169 unique point mutation sites. We counted the numbers and calculated the minor allele frequency (MAF) of each mutation type. Results: Nearly half of the point mutations are C–T mismatches and 20% are A–G mismatches. The MAF of C–T and A–G mismatches is significantly higher than MAF of other mutation types. Conclusion: The excessive C–T mismatches do not resemble the random mutation profile. They are likely to be caused by the cytosine-to-uridine deamination system in hosts.

scholarly journals Associations between Common Genetic Polymorphisms in Angiopoietin-Like Proteins 3 and 4 and Lipid Metabolism and Adiposity in European Adolescents and Adults

2009 ◽  
Vol 94 (12) ◽  
pp. 5070-5077 ◽  
Author(s):  
Vanessa Legry ◽  
Szilvia Bokor ◽  
Dominique Cottel ◽  
Laurent Beghin ◽  
Giovina Catasta ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Allele Frequency ◽  
Genetic Polymorphisms ◽  
Body Fat ◽  
Minor Allele Frequency ◽  
Cholesterol Metabolism ◽  
Hdl Cholesterol ◽  
Minor Allele ◽  
Peroxisome Proliferator ◽  
Independent Population

Context: Plasma-borne angiopoietin-like proteins (ANGPTL) act as endocrine factors on their target tissues. Because ANGPTL3 and ANGPTL4 play important roles in lipid metabolism and the regulation of adiposity in mice, we hypothesized that genetic variability at the ANGPTL3 and ANGPTL4 genes loci might influence lipid metabolism and fat deposition in humans. Objective: The aim of the study was to examine the association between ANGPTL3 and ANGPTL4 genetic polymorphisms and metabolic phenotypes in adolescent and adult samples. Design and Participants: Two independent population-based studies, one composed of 1144 adolescents (mean age, 14.8 ± 1.4 yr) from nine European countries (the HELENA study) and the other composed of 1155 adults (age range, 35–65 yr) from Northern France (the MONICA Lille study), were genotyped for one ANGPTL3 polymorphism and four ANGPTL4 polymorphisms. Results: The ANGPTL3 rs11207997 polymorphism (minor allele frequency, 0.32) was associated with lower plasma HDL-cholesterol and apolipoprotein A-I levels in both adolescents (P = 0.0004, P = 0.00006, respectively) and adults (P = 0.03, P = 0.02, respectively). The ANGPTL4 rs4076317 polymorphism (minor allele frequency, 0.29) was associated with a higher percentage of body fat (P = 0.02) in adolescents and a higher waist-to-hip ratio (in interaction with the peroxisome proliferator-activated receptor γ Pro12Ala polymorphism) in adults (P = 0.0004). Conclusion: The present study underlines the role of ANGPTL3 in HDL-cholesterol metabolism as early as in adolescence. Our data also suggest possible associations between ANGPTL4 polymorphisms and body fat, but these findings require replication.

Effect of quality control, density and allele frequency of markers on the accuracy of genomic prediction for complex traits in Nellore cattle

2019 ◽  
Vol 59 (1) ◽  
pp. 48 ◽  
Author(s):  
Tiago Bresolin ◽  
Guilherme Jordão de Magalhães Rosa ◽  
Bruno Dourado Valente ◽  
Rafael Espigolan ◽  
Daniel Gustavo Mansan Gordo ◽  
...  
Keyword(s):  
Quality Control ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Genomic Prediction ◽  
High Density ◽  
Minor Allele ◽  
Call Rate ◽  
Genotyping Assay ◽  
Nellore Cattle ◽  
Genomic Predictions

This study was designed to test the impact of quality control, density and allele frequency of single nucleotide polymorphisms (SNP) markers on the accuracy of genomic predictions, using three traits with different heritabilities and two methods of prediction in a Nellore cattle population genotyped with the Illumina Bovine HD Assay. A total of 1756; 3150 and 3119 records of age at first calving (AFC); weaning weight (WW) and yearling weight (YW), respectively, were used. Three scenarios with different exclusion thresholds for minor allele frequency (MAF), deviation from Hardy–Weinberg equilibrium (HWE) and correlation between SNP pairs (r2) were constructed for all traits: (1) high rigor (S1): call rate <0.98, MAF <0.05, HWE with P <10−5, and r2 >0.999; (2) Moderate rigor (S2): call rate <0.85 and MAF <0.01; (3) Low rigor (S3): only non-autosomal SNP and those mapped on the same position were excluded. Additionally, to assess the prediction accuracy from different markers density, six panels (10K, 50K, 100K, 300K, 500K and 700K) were customised using the high-density genotyping assay as reference. Finally, from the markers available in high-density genotyping assay, six groups (G) with different minor allele frequency bins were defined to estimate the accuracy of genomic prediction. The range of MAF bins was approximately equal for the traits studied: G1 (0.000–0.009), G2 (0.010–0.064), G3 (0.065–0.174), G4 (0.175–0.325), G5 (0.326–0.500) and G6 (0.000–0.500). The Genomic Best Linear Unbiased Predictor and BayesCπ methods were used to estimate the SNP marker effects. Five-fold cross-validation was used to measure the accuracy of genomic prediction for all scenarios. There were no effects of genotypes quality control criteria on the accuracies of genomic predictions. For all traits, the higher density panel did not provide greater prediction accuracies than the low density one (10K panel). The groups of SNP with low MAF (MAF ≤0.007 for AFC, MAF ≤0.009 for WW and MAF ≤0.008 for YW) provided lower prediction accuracies than the groups with higher allele frequencies.

scholarly journals Corrigendum: Exact Distribution of Linkage Disequilibrium in the Presence of Mutation, Selection, or Minor Allele Frequency Filtering

2020 ◽  
Vol 11 ◽  
Author(s):  
Jiayi Qu ◽  
Stephen D. Kachman ◽  
Dorian Garrick ◽  
Rohan L. Fernando ◽  
Hao Cheng
Keyword(s):  
Linkage Disequilibrium ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Exact Distribution ◽  
Minor Allele ◽  
Frequency Filtering

scholarly journals Post-mortem genetic investigation of cardiac disease–associated genes in sudden infant death syndrome (SIDS) cases

2020 ◽  
Vol 135 (1) ◽  
pp. 207-212 ◽  
Author(s):  
Jasmin Köffer ◽  
Stefanie Scheiper-Welling ◽  
Marcel A. Verhoff ◽  
Thomas Bajanowski ◽  
Silke Kauferstein
Keyword(s):  
Allele Frequency ◽  
Sudden Infant Death Syndrome ◽  
Minor Allele Frequency ◽  
Cardiac Disease ◽  
Infant Death ◽  
Heart Diseases ◽  
Sudden Infant Death ◽  
Minor Allele ◽  
Sudden Infant ◽  
Variant Of Uncertain Significance

AbstractThe sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be “potentially informative.” The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved.

scholarly journals Functional polymorphisms affecting the clinically important arginine-137 residue of AVPR2 do not influence serum sodium concentration at the population level

2013 ◽  
Vol 45 (6) ◽  
pp. 210-216 ◽  
Author(s):  
Yi Fu ◽  
Tim Cheetham ◽  
David Bourn ◽  
Eric Orwoll ◽  
David M. Cohen
Keyword(s):  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Serum Sodium ◽  
Population Distribution ◽  
Sodium Concentration ◽  
Protein Product ◽  
Minor Allele ◽  
Serum Sodium Concentration ◽  
Interindividual Variation ◽  
Functional Polymorphisms

The protein product of the AVPR2 gene, coding for the arginine vasopressin receptor type 2, is essential for vasopressin-dependent concentration of the urine. The arginine residue at position 137 in the protein product of this gene is uniquely pivotal for function. The R137H mutant inactivates the receptor conferring congenital nephrogenic diabetes insipidus, whereas activating mutations at this same residue (i.e., R137C and R137L) confer pathological water retention in the nephrogenic syndrome of inappropriate antidiuresis. These mutations were discovered in human subjects with conspicuous phenotypes in clinical water balance. Prevalence of these polymorphisms among asymptomatic individuals has not been assessed, nor has their contribution to broad interindividual variation in serum sodium concentration; no data addressing minor allele frequency are available. We genotyped two large cohorts using a validated high-throughput Pyrosequencing-based assay that we designed to capture the totality of pathological variation at this important residue. In the Osteoporotic Fractures in Men (MrOS) Study, all participants were male (i.e., hemizygous for AVPR2 gene on the X-chromosome), and participants were oversampled at the extremes of the population distribution for serum sodium concentration. In the Offspring Cohort of the Framingham Heart Study, male and female participants were genotyped. No pathological variants affecting R137 were detected among the 5,142 AVPR2 alleles successfully genotyped. Even at the population extremes of serum sodium distribution, we estimate minor allele frequency < 0.06%. We conclude that these disease-associated variants are exceedingly uncommon and do not contribute broadly to interindividual variability in serum sodium concentration or to its heritability.

scholarly journals Population structure at different minor allele frequency levels

2014 ◽  
Vol 8 (S1) ◽  
Author(s):  
Omar De la Cruz ◽  
Paola Raska
Keyword(s):  
Population Structure ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Minor Allele
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