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Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease

Quantitative Biology 2021年第2期9卷 216-227页

作者： Mo Li Xue Zeng Chentian Jin Sheng Chih Jin Weilai Dong Martina Brueckner Richard Lifton Qiongshi Lu Hongyu Zhao Department of Biostatistics Yale School of Public HealthNew HavenCT 06510USA Department of genetics Yale UniversityNew HavenCT 06510USA Department of Molecular Cellular&Developmental BiologyYale UniversityCT 06510USA Department of genetics Washington University School of MedicineSt LouisMO 63110USA Department of Pediatrics Yale UniversityNew HavenCT 06510USA laboratory of Human genetics and Genomics Rockefeller UniversityNew YorkNY 10065USA Department of Biostatistics and Medical Informatics University of Wisconsin-MadisonMadisonWl 53792USA Program of Computational Biology and Bioinformatics Yale UniversityNew HavenCT 06510USA

Background:Whole-exome sequencing(WES)studies have identified multiple genes enriched for de novo mutations(DNMs)in congenital heart disease(CHD)***,risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each ***:In this manuscript,we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes de novo and rare transmitted *** integrative modeling of multiple types of genetic variants,gene-level annotations,and reference data from large population cohorts,our method accurately characterizes the expected frequencies of both de novo and transmitted variants and shows improved statistical power compared to analyses based on DNMs ***:Applied to WES data of 2,645 CHD proband-parent trios,our method identified 15 significant genes,half of which are novel,leading to new insights into the genetic bases of ***:These results showcase the power of integrative analysis of transmitted and de novo variants for disease gene discovery.

关键词： rare variants gene-level association test congenital heart disease de novo mutation

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Leber’s遗传性视神经病变分子致病机制研究(英文)

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眼视光学杂志 2006年第6期8卷 341-348页

作者：瞿佳管敏鑫 School of Ophthalmology and Optometry Wenzhou Medical College Wenzhou China325003Zhejiang Provincial Key Laboratory of Medical Genetics School of Life Sciences Wenzhou Medical College Wenzhou China325003 School of Ophthalmology and Optometry Wenzhou Medical College Wenzhou China325003 Division of Human Genetics Cincinnati Children’s Hospital Medical Center Cincinnati Ohio 45229 USAZhejiang Provincial Key Laboratory of Medical Genetics School of Life Sciences Wenzhou Medical College Wenzhou China325003Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio 45229 USA

Leber’s遗传性视神经病变(Leber’s hereditary optic neuropathy,LHON)是一种较常见的引起视神经萎缩的遗传性疾病。该病主要引起双侧中心视力丧失,造成永久性的严重视觉障碍,常常发生在一些即将或已工作或上学的年轻人身上,以及在对... 详细信息

Leber’s遗传性视神经病变(Leber’s hereditary optic neuropathy,LHON)是一种较常见的引起视神经萎缩的遗传性疾病。该病主要引起双侧中心视力丧失,造成永久性的严重视觉障碍,常常发生在一些即将或已工作或上学的年轻人身上,以及在对该病患者家系中其他成员进行遗传病检查时发现。在一些LHON家系中,视觉障碍的患者呈现母系遗传方式,这表明线粒体DNA(mitochondrial DNA,mtDNA)是该病的分子遗传基础。至今为止,在世界各地不同家系报道中已经发现大约有35个与LHON相关的突变位点,其中ND1G3460A、ND4G11778A、ND6T14484C为三个公认的原发突变位点,均参与呼吸链复合体I的亚基编码。在不同种族发病统计中,其中大约50%的LHON由三个原发致病突变中的一个所致,尤为G11778A突变为主。引人注意的是,LHON家系携带相同突变的母系成员表现出不同的外显率、表现度(如发病严重程度、发病年龄、视力丧失进展程度)。不完全和不同的外显率以及轻度的生化影响说明mtDNA突变本身不足以产生临床表型,其他因素(如环境、核修饰基因、线粒体单体型等)可能影响LHON的外显率和表型表达。

关键词： Leber’s遗传性视神经病变脱氧核糖核酸,线粒体致病机制

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SLC26A4 mutation testing for hearing loss associated with enlargement of the vestibular aqueduct

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World Journal of Otorhinolaryngology 2013年第2期3卷 26-34页

作者： Taku Ito Julie Muskett Parna Chattaraj Byung Yoon Choi Kyu Yup Lee Christopher K Zalewski Kelly A King Xiangming Li Philine Wangemann Thomas Shawker Carmen C Brewer Seth L Alper Andrew J Griffith Otolaryngology Branch National Institute on Deafness and Other Communication Disorders National Institutes of Health Rockville MD 20850 United States laboratory of Molecular genetics National Institute on Deafness and Other Communication Disorders National Institutes of Health Rockville MD 20850 United States Anatomy and Physiology Department Kansas State University Manhattan KS 66506 United States Diagnostic Radiology Department Warren G. Magnuson Clinical Center National Institutes of Health Bethesda MD 20892 United States Renal Division Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 02215 United States

nPendred syndrome （PS） is characterized by autosomal recessive inheritance of goiter associated with a defect of iodide organification, hearing loss, enlargement of the vestibular aqueduct （EVA）, and mutations of the SLC26A4 gene. However, not all EVA patients have PS or SLC26A4 mutations. Two mutant alleles of SLC26A4 are detected in 1/4 of North American or European EVA populations, one mutant allele is detected in another 1/4 of patient populations, and no mutations are de-tected in the other 1/2. The presence of two mutant al-leles of SLC26A4 is associated with abnormal iodide or-ganification, increased thyroid gland volume, increased severity of hearing loss, and bilateral EVA. The pres-ence of a single mutant allele of SLC26A4 is associated with normal iodide organification, normal thyroid gland volume, less severe hearing loss and either bilateral or unilateral EVA. When other underlying correlations are accounted for, the presence of a cochlear malformation or the size of EVA does not have an effect on hearing thresholds. This is consistent with observations of an Slc26a4 mutant mouse model of EVA in which hearing loss is independent of endolymphatic hydrops or in-ner ear malformations. Segregation analyses of EVA in families suggest that the patients carrying one mutant allele of SLC26A4 have a second, undetected mutant allele of SLC26A4, and the probability of a sibling hav-ing EVA is consistent with its segregation as an autoso-mal recessive trait. Patients without any mutations are an etiologically heterogeneous group in which siblings have a lower probability of having EVA. SLC26A4 muta-tion testing can provide prognostic information to guide clinical surveillance and management, as well as the probability of EVA affecting a sibling.

关键词： SLC26A4 Pendred syndrome genetic test-ing Goiter Hearing loss Vestibular aqueduct Genotype-phenotype correlation

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Breast Cancer Risk Genes-Association Analysis in More than 113,000 Women

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四川生理科学杂志 2021年第1期43卷 7-7页

作者： Leila Dorling The authors' affiliations are as follows: the Centre for Cancer genetic Epidemiology Departments of Public Health and Primary Care (L.D. S. Carvalho J.A. K.A.P. Q.W. M.K.B. J.D. B.D. N. Mavaddat K. Michailidou A.C.A. P.D.P.P. D.F.E.) and Oncology (C.L. P.A.H. C. Baynes D.M.C. L.F. V.R. M. Shah P.D.P.P. A.M.D. D.F.E.) University of Cambridge Cambridge the Centre for Genomic and Experimental Medicine MRC Institute of Genetics and Molecular Medicine (A. Campbell D.J.P.) and the Centre for Cognitive Ageing and Cognitive Epidemiology Department of Psychology (D.J.P.) University of Edinburgh the Cancer Research UK Edinburgh Centre (D.A.C. J.F.) and the Usher Institute of Population Health Sciences and Informatics University of Edinburgh Medical School (A. Campbell J.F.) Edinburgh the Divisions of Informatics Imaging and Data Sciences (E.F.H.) Cancer Sciences (A. Howell) Population Health Health Services Research and Primary Care (A. Lophatananon K. Muir) and Evolution and Genomic Sciences School of Biological Sciences (W.G.N. E.M.V. D.G.E.) University of Manchester the NIHR Manchester Biomedical Research Unit (E.F.H.) and the Nightingale Breast Screening Centre Wythenshawe Hospital (E.F.H. H.I.) Academic Health Science Centre and North West Genomics Laboratory Hub and the Manchester Centre for Genomic Medicine St. Mary's Hospital Manchester University NHS Foundation Trust (W.G.N. E.M.V. D.G.E.) Manchester the School of Cancer and Pharmaceutical Sciences Comprehensive Cancer Centre Guy's Campus King's College London London (E.J.S.) the Institute of Cancer and Genomic Sciences University of Birmingham Birmingham (I.T.) and the Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford (I.T.) - all in the United Kingdom the Human Genotyping-CEGEN Unit Human Cancer Genetic Program (A.G.-N. M.R.A. N.Á. B.H. R.N.-T.) and the Human Genetics Group (V.F. A.O. J.B.) Spanish National Cancer Research

Background:genetic testing for breast cancer susceptibility is widely used,but for many genes,evidence of an association with breast cancer is weak,underlying risk estimates are imprecise,and reliable subtype-specific risk estimates are ***:We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 *** separate analyses for protein-truncating variants and rare missense variants in these genes,we estimated odds ratios for breast cancer overall and tumor *** evaluated missense-variant associations according to domain and classification of pathogenicity.

关键词： cancer Breast Cancer

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