scholarly journals Transcript-Specific Loss-of-Function Variants in VPS16 Are Enriched in Patients With Dystonia

2021 ◽  
Vol 8 (1) ◽  
pp. e644
Author(s):  
Joohyun Park ◽  
Annemarie Reilaender ◽  
Jan N. Petry-Schmelzer ◽  
Petra Stöbe ◽  
Isabell Cordts ◽  
...  
Keyword(s):  
Fisher Exact Test ◽  
Data Sets ◽  
Variant Interpretation ◽  
Loss Of Function ◽  
Splice Isoforms ◽  
Exact Test ◽  
Expression Levels ◽  
Genome Data ◽  
Statistical Measures ◽  
Clinical Description

Background and ObjectivesOur objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare VPS16 variants observed in patients with dystonia and patients without dystonia, elaborate on our interpretation of VPS16 variants affecting different transcripts, and provide detailed clinical description of the movement disorder caused by VPS16 variants.MethodsIn-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in VPS16. Using pext (proportion expressed across transcripts) values from the Genome Aggregation Database (gnomAD), we differentiated variants affecting weakly and highly expressed exons/transcripts and applied statistical measures to systematically identify disease-associated genetic variation among patients with dystonia (n = 280).ResultsSix different heterozygous pLoFs in VPS16 transcripts were identified in 13 individuals. Three of these pLoFs occurred in 9 individuals with different phenotypes, and 3 pLoFs were identified in 4 unrelated individuals with early-onset dystonia. Although pLoFs were enriched in the dystonia cohort (n = 280; p = 2.04 × 10−4; 4/280 cases vs 9/11,259 controls; Fisher exact test), it was not exome-wide significant. According to the pext values in gnomAD, all 3 pLoFs observed in the patients with dystonia were located in the highly expressed canonical transcript ENST00000380445.3, whereas 2 of 3 pLoFs detected in 8 individuals without dystonia were located in the first exon of the noncanonical transcript ENST00000380443.3 that is weakly expressed across all tissues. Taking these biological implications into account, pLoFs involving the canonical transcript were exome-wide significantly enriched in patients with dystonia (p = 1.67 × 10−6; 4/280 cases vs 1/11,259 controls; Fisher exact test). All VPS16 patients showed mild progressive dystonia with writer's cramp as the presenting symptom between age 7 and 34 years (mean 20 years) that often progressed to generalized dystonia and was even accompanied by hyperkinetic movements and myoclonus in 1 patient.DiscussionOur data provide strong evidence for VPS16 pLoFs to be implicated in dystonia and knowledge on exon resolution expression levels as well as statistical measures proved to be useful for variant interpretation.

Mapping cis-acting regulatory variation in recombinant congenic strains

2006 ◽  
Vol 25 (2) ◽  
pp. 294-302 ◽  
Author(s):  
Peter D. Lee ◽  
Bing Ge ◽  
Celia M. T. Greenwood ◽  
Donna Sinnett ◽  
Yannick Fortin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Fisher Exact Test ◽  
Donor Strain ◽  
Exact Test ◽  
Expression Levels ◽  
Cis Acting ◽  
Congenic Strains ◽  
Recombinant Congenic Strains ◽  
Genetic Context

We present an integrated approach for the enriched detection of genes subject to cis-acting variation in the mouse genome. Gene expression profiling was performed with lung tissue from a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J inbred mouse strains. A multiple-regression model measuring the association between gene expression level, donor strain of origin (DSO), and predominant strain background identified over 1,500 genes ( P < 0.05) whose expression profiles differed according to the DSO. This model also identified over 1,200 genes whose expression showed dependence on background ( P < 0.05), indicating the influence of background genetic context on transcription levels. Sequences obtained from 1-kb segments of 3′-untranslated regions identified single nucleotide polymorphisms in 64% of genes whose expression levels correlated with DSO status, compared with 29% of genes that displayed no association ( P < 0.01, Fisher exact test). Allelic imbalance was identified in 50% of genes positive for expression-DSO association, compared with 22% of negative genes ( P < 0.05, Fisher exact test). Together, these results demonstrate the utility of RCS mice for identifying the roles of proximal genetic determinants and background genetic context in determining gene expression levels. We propose the use of this integrated experimental approach in multiple tissues from this and other RCS panels as a means for genome-wide cataloging of genetic regulatory mechanisms in laboratory strains of mice.

scholarly journals Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Precocious Puberty ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Fisher Exact Test ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Exact Test ◽  
First Case

Abstract Background Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2. Methods We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD). Results No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD). Conclusions As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

scholarly journals Molecular Screening of PROKR2 Gene in Girls with Idiopathic Central Precocious Puberty.

2020 ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Precocious Puberty ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Fisher Exact Test ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Exact Test ◽  
First Case

Abstract Background: Prokineticin receptor 2 (PROKR2) loss of function mutations have been describedas cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty(CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-oldgirl. No other cases have been reported yet. This study performs a molecular screening ingirls with early onset CPP (breast budding before 6 years of age) to identify possiblealterations in PROKR2.Methods: We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels >0.3IU/L or peak-LH>5IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD).Results: No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD).Conclusions: As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 donot seem to be a frequent cause of CPP in girls.

scholarly journals The Genes—Candidates for Prognostic Markers of Metastasis by Expression Level in Clear Cell Renal Cell Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 30 ◽  
Author(s):  
Natalya Apanovich ◽  
Maria Peters ◽  
Pavel Apanovich ◽  
Danzan Mansorunov ◽  
Anna Markova ◽  
...  
Keyword(s):  
Renal Cell ◽  
Prognostic Markers ◽  
Clear Cell ◽  
Cell Cancer ◽  
Fisher Exact Test ◽  
Cell Renal Cell Carcinoma ◽  
Exact Test ◽  
Expression Levels ◽  
First Time ◽  
Gene Expression Levels

The molecular prognostic markers of metastasis are important for personalized approaches to clear cell renal cell carcinoma (ccRCC) treatment but markers for practical use are still missing. To address this gap we studied the expression of ten genes—CA9, NDUFA4L2, VWF, IGFBP3, BHLHE41, EGLN3, SAA1, CSF1R, C1QA, and FN1—through RT-PCR, in 56 ccRCC patients without metastases and with metastases. All of these, excluding CSF1R, showed differential and increased (besides SAA1) expression in non-metastasis tumors. The gene expression levels in metastasis tumors were decreased, besides CSF1R, FN1 (not changed), and SAA1 (increased). There were significant associations of the differentially expressed genes with ccRCC metastasis by ROC analysis and the Fisher exact test. The association of the NDUFA4L2, VWF, EGLN3, SAA1, and C1QA expression with ccRCC metastasis is shown for the first time. The CA9, NDUFA4L2, BHLHE4, and EGLN3 were distinguished as the strongest candidates for ccRCC metastasis biomarkers. We used an approach that presupposed that the metastasis marker was the expression levels of any three genes from the selected panel and received sensitivity (88%) and specificity (73%) levels with a relative risk of RR > 3. In conclusion, a panel of selected genes—the candidates in biomarkers of ccRCC metastasis—was created for the first time. The results might shed some light on the ccRCC metastasis processes.

scholarly journals Identification of Peptidyl-Prolyl Cis-Trans Isomerase-Like 4 as a Disease Causing Gene in Intracranial Aneurysms and its Role in Vertebrate CNS Specific Angiogenesis

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Tanyeri Barak ◽  
Adife Gulhan Ercan Sencicek ◽  
Danielle F Miyagishima ◽  
Octavian Henegariu ◽  
Ketu Mishra Gorur ◽  
...  
Keyword(s):  
Mrna Stability ◽  
Rna Binding ◽  
The United States ◽  
Rna Modification ◽  
Control Group ◽  
Fisher Exact Test ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Exact Test

Abstract INTRODUCTION Intracranial aneurysm (IA) is a significant health burden affecting nearly 6 million people in the United States with an estimated prevalence of 3.2% worldwide. Using whole exome sequencing (WES) of 728 European IA cases, we identified damaging mutations in and RNA binding protein peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4) in both familial and sporadic IA cases. METHODS We performed WES in 728 European IA cases followed by a mutational burden analysis between IA cases and a European (Finnish + Non-Finnish) control group of 1443 unaffected individuals, and European subjects (non-Finnish + Finnish) in the ExAC and gnomAD databases. Fisher exact test was used to determine the significance of the enrichment of rare (ExAC MAF <0.0001) and deleterious variants consisting of loss of function and deleterious missense mutations (MetSVM-D). Mutant ppil4 lines were generated using Crispr-CAS9 in zebrafish and X.tropicalis. RNA-seq and Slam-Seq were performed to identify transcriptome-wide changes in RNA half-life mediated by PPIL4. RESULTS Burden analysis revealed a significant enrichment of rare and deleterious PPIL4 variants in European IA cases when compared to 1443 controls (OR = INF., Fisher P = 3.17 × 10–4), ExAC (OR = 12.26, Fisher P = 5 × 10–4) or gnomAD (OR = 13.14, Fisher P = 3.4 × 10–4). PPIL4 mutants both in zebrafish and X.tropicalis models displayed cerebral hemorrhage and cerebrovascular simplification. Slam-seq analysis revealed that PPIL4 promotes mRNA stability of the genes implicated in VEGF signaling (FDR = 3.75E-07) and Focal adhesion pathways (FDR = 2.04E-06). CONCLUSION In this study, we identified PPIL4 as a candidate gene in IA pathogenesis and demonstrated morphological and hemodynamic impairment in vivo upon abrogating PPIL4 in 2 vertebrate models. Furthermore, we demonstrated that PPIL4 plays a major role in CNS angiogenesis and IA pathogenesis through promoting mRNA stability of key angiogenesis related genes, emphasizing the role of post-transcriptional RNA modification in cerebrovascular development and pathologies.

Venous Thromboembolism and High Grade Gliomas

1993 ◽  
Vol 70 (03) ◽  
pp. 393-396 ◽  
Author(s):  
Mandeep S Dhami ◽  
Robert D Bona ◽  
John A Calogero ◽  
Richard M Hellman
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Medical Center ◽  
Significant Risk ◽  
Bleeding Complications ◽  
Fisher Exact Test ◽  
High Grade ◽  
Chi Square ◽  
Exact Test ◽  
High Grade Gliomas

SummaryA retrospective study was done to determine the incidence of and the risk factors predisposing to clinical venous thromboembolism (VTE) in patients treated for high grade gliomas. Medical records of 68 consecutive patients diagnosed and treated at Saint Francis Hospital and Medical Center from January 1986 to June 1991 were reviewed. The follow up was to time of death or at least 6 months (up to December 1991). All clinically suspected episodes of VTE were confirmed by objective tests. Sixteen episodes of VTE were detected in 13 patients for an overall episode rate of 23.5%. Administration of chemotherapy (p = 0.027, two tailed Fisher exact test) and presence of paresis (p = 0.031, two tailed Fisher exact test) were statistically significant risk factors for the development of VTE. Thrombotic events were more likely to occur in the paretic limb and this difference was statistically significant (p = 0.00049, chi square test, with Yates correction). No major bleeding complications were seen in the nine episodes treated with long term anticoagulation.We conclude that venous thromboembolic complications are frequently encountered in patients being treated for high grade gliomas and the presence of paresis and the administration of chemotherapy increases the risk of such complications.

Electronic cigarettes: How confident and effective are allergists, pulmonologists, and primary care physicians in their practice behavior?

2020 ◽  
Vol 41 (3) ◽  
pp. 192-197
Author(s):  
Sherry S. Zhou ◽  
Alan P. Baptist
Keyword(s):  
Primary Care ◽  
Primary Care Physicians ◽  
Electronic Cigarettes ◽  
The United States ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Knowledge And Beliefs ◽  
Tobacco Cigarette ◽  
Number Of Patients ◽  
Personal Use

Background: There has been a striking increase in electronic cigarette (EC) use in the United States. The beliefs and practices toward ECs among physicians are unknown. Objective: The purpose of this study was to investigate EC practice patterns among allergists, pulmonologists, and primary care physicians. Methods: An anonymous survey was sent to physicians. The survey contained 32 questions and addressed issues related to demographics, cessation counseling behaviors, personal use, and knowledge and beliefs about ECs. Statistical analysis was performed by using analysis of variance, the Pearson χ2 test, Fisher exact test, and logistic regression. Results: A total of 291 physicians completed the survey (222 primary care physicians, 33 pulmonologists, and 36 allergists) for a response rate of 46%. The allergists asked about tobacco cigarette use as frequently as did the pulmonologists and more than the primary care physicians (p < 0.001), but they rarely asked about EC use. The pulmonologists scored highest on self-reported knowledge on ECs, although all the groups answered <40% of the questions correctly. The allergists did not feel as comfortable about providing EC cessation counseling as did the pulmonologists and primary care physicians (p < 0.001). All three groups were equally unlikely to recommend ECs as a cessation tool for tobacco cigarette users. Conclusion: Allergists lacked knowledge and confidence in providing education and cessation counseling for EC users. As the number of patients who use these products continues to increase, there is an urgent need for all physicians to be comfortable and knowledgeable with counseling about ECs.

Perbedaan Kontaminasi Bacteria Staphylococcus sp di Denominasi Uang Kertas Rupiah di Warung Jalan Adi Sucipto Kota Pontianak

2018 ◽  
Vol 1 (2) ◽  
pp. 166
Author(s):  
Sutriswanto Sutriswanto ◽  
Sugito Sugito
Keyword(s):  
Research Method ◽  
Sampling Technique ◽  
Cluster Sampling ◽  
Fisher Exact Test ◽  
Infectious Agents ◽  
Exact Test ◽  
Purposive Sampling ◽  
Paper Money

Abstract: Staphylococcus is a cause of infection. Infection can be transmitted from a source by an indirect through fomite. Paper money can act as transmission of infectious agents, money acts as a fomite. Smaller denominations of value have higher contamination. This study aims to analyze differences in contamination bacterial Staphylococcus sp on denomination of paper money Rp.2.000, 5.000, Rp.10,000 and Rp.20.000 that currently shop on Adi Sucipto street town Pontianak. The research method used in this research is in the form of difference and the sample in this research is denomination of paper money curently with sampling technique using cluster sampling. Checkup of Staphylococcus spon denomination of paper money using rinse method. On these result of study, denomination of paper money Rp.2.000 that is contaminated staphylococcus sp is 80%, denomination of paper money Rp.5.000 that is contaminated staphylococcus sp is 70%, denomination of paper money Rp.10.000 and Rp.20.000 that is contaminated staphylococcus sp is 80%. The data from result of study has been obtained were analyzed statistically by using fisher exact test, the result of p (0,477) >α (0,05) which mean as H1 is rejected. So it can be concluded there is no difference of contamination bacteria staphylococcus sp on denominations of paper money rupiah.Abstrak: Staphylococcus merupakan penyebab terjadinya infeksi. Infeksi dapat ditularkan dari suatu sumber dengan mekanisme tidak langsung melalui fomite. Uang kertas dapat bertindak sebagai transmisi agens infeksius ,uang berperan sebagai fomite. Pecahan uang yang lebih kecil nilainya memiliki kontaminasi yang lebih tinggi. Penelitian ini bertujuan untuk menganalisis perbedaan cemaran bakteri Staphylococcus sp pada pecahan uang kertas Rp.2.000, 5.000, Rp.10.000 dan Rp.20.000 yang beredar di warung jalan Adi Sucipto kota Pontianak. Metode penelitian yang digunakan dalam penelitian berbentuk komperatif dan sampel pada penelitian ini adalah pecahan uang kertas rupiah dengan.teknik pengambilan sampel menggunakan purposive sampling. Pemeriksaan Staphylococcus sp pada pecahan uang kertas rupiah menggunakan metode rinse. Pada hasil penelitian pecahan uang kertas Rp.2.000 yang tercemar staphylococcus sp adalah 80%, pecahan uang kertas Rp.5.000 yang tercemar staphylococcus spadalah 70%, pecahan uang kertas Rp.10.000 dan Rp.20.000 yang tercemar staphylococcus spadalah 50%. Berdasarkan data dari hasil penelitian yang telah didapat dianalisis menggunakan uji statistik fisher exact, didapatkan hasil p (0,477) >α (0,05) yang diartikan sebagai H1 ditolak. Sehingga dapat disimpulkan tidak ada perbedaan cemaran bakteri staphylococcus sp pada pecahan uang kertas rupiah.

Characteristics of Physician Relocation Following Hurricane Katrina

2009 ◽  
Vol 95 (1) ◽  
pp. 6-12
Author(s):  
Kusuma Madamala ◽  
Claudia R. Campbell ◽  
Edbert B. Hsu ◽  
Yu-Hsiang Hsieh ◽  
James James
Keyword(s):  
Hurricane Katrina ◽  
Gulf Coast ◽  
General Medicine ◽  
The United States ◽  
Lessons Learned ◽  
Bivariate Analysis ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Factors Associated ◽  
The Impact

ABSTRACT Introduction: On Aug. 29, 2005, Hurricane Katrina made landfall along the Gulf Coast of the United States, resulting in the evacuation of more than 1.5 million people, including nearly 6000 physicians. This article examines the relocation patterns of physicians following the storm, determines the impact that the disaster had on their lives and practices, and identifies lessons learned. Methods: An Internet-based survey was conducted among licensed physicians reporting addresses within Federal Emergency Management Agency-designated disaster zones in Louisiana and Mississippi. Descriptive data analysis was used to describe respondent characteristics. Multivariate logistic regression was performed to identify the factors associated with physician nonreturn to original practice. For those remaining relocated out of state, bivariate analysis with x2 or Fisher exact test was used to determine factors associated with plans to return to original practice. Results: A total of 312 eligible responses were collected. Among disaster zone respondents, 85.6 percent lived in Louisiana and 14.4 percent resided in Mississippi before the hurricane struck. By spring 2006, 75.6 percent (n = 236) of the respondents had returned to their original homes, whereas 24.4 percent (n = 76) remained displaced. Factors associated with nonreturn to original employment included family or general medicine practice (OR 0.42, 95 percent CI 0.17–1.04; P = .059) and severe or complete damage to the workplace (OR 0.24, 95 percent CI 0.13–0.42; P &lt; .001). Conclusions: A sizeable proportion of physicians remain displaced after Hurricane Katrina, along with a lasting decrease in the number of physicians serving in the areas affected by the disaster. Programs designed to address identified physician needs in the aftermath of the storm may give confidence to displaced physicians to return.

scholarly journals E-health and health literacy of young adult Ukrainian female immigrants and Polish counterparts

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
Y Krasko ◽  
J Marianowska ◽  
M Duplaga
Keyword(s):  
Health Status ◽  
Health Literacy ◽  
Young Adult ◽  
Online Survey ◽  
Health Behaviours ◽  
Study Groups ◽  
University Education ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Ehealth Literacy

Abstract Background According to recent projections, even 10% of Polish gross domestic product is contributed by Ukrainian immigrants. There is also a considerable number of Ukrainians continuing university education in Poland. The level of health literacy in Ukrainian society has not been studied so far. The aim of the study was the comparison of health literacy (HL) and e-health literacy (eHL) of young adult Ukrainian (UA) women with their Polish (PL) counterparts Methods A snowball technique was used to recruit a sample of UA women working or studying in Poland to the Internet-based survey. The questionnaire used in the study consisted of the 16-item European HL Survey questionnaire (HLS-EU-16), eHealth Literacy Scale (eHEALS), the set of the questions asking about health behaviours (HB), self-assessment of health status (HS) and items exploring sociodemographic variables. For comparison, the data of an age-matched sample of 100 respondents was extracted from the online survey performed in a representative sample of PL women. Results The mean age (standard deviation, SD) of 57 UA respondents was 20.23 (1.78) years and in Polish sample 20.25 (1.79). HL did not differ between both groups (11.06 (4.22) vs 11.44 (4.34), respectively, p = 0.53), but eHL was significantly lower in UA group (25.91 (5.36) vs 28.17 (5.37), U Mann-Whitney test, p = 0.01). Only 58.5% of UA respondents vs 80.5% of PL ones assessed their HS as at least good (Fisher exact test, p &lt; 0.001). The rates of active smoking (34.6% vs. 35.0%, p = 0.55), using e-cigarettes (35.3% vs 34.0%, p = 0.99), frequent alcohol consumption (26.9% vs. 20%, p = 0.41), and intensive physical activity (49.0% vs. 38.0%, p = 0.22) did not differ between study groups. Conclusions Young UA women show lower eHL than PL counterparts. Although HL and HB in both groups did not differ significantly, UA respondents have assessed their HS much lower than PL participants. Key messages E-health literacy and self-assessed health status were significantly lower among young Ukrainian than among Polish women. Both groups did not differ for health literacy and health behaviours.

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