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https://www.readbyqxmd.com/read/28717674/exactly-zero-or-once-a-clinically-helpful-guide-to-assessing-genetic-variants-in-mild-epilepsies
#1
Caitlin A Bennett, Slavé Petrovski, Karen L Oliver, Samuel F Berkovic
OBJECTIVE: To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population. METHODS: We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or ≥4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals...
August 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28716533/novel-ubqln2-mutations-linked-to-amyotrophic-lateral-sclerosis-and-atypical-hereditary-spastic-paraplegia-phenotype-through-defective-hsp70-mediated-proteolysis
#2
Elisa Teyssou, Laura Chartier, Maria-Del-Mar Amador, Roselina Lam, Géraldine Lautrette, Marie Nicol, Selma Machat, Sandra Da Barroca, Carine Moigneu, Mathilde Mairey, Thierry Larmonier, Safaa Saker, Christelle Dussert, Sylvie Forlani, Bertrand Fontaine, Danielle Seilhean, Delphine Bohl, Séverine Boillée, Vincent Meininger, Philippe Couratier, François Salachas, Giovanni Stevanin, Stéphanie Millecamps
Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c...
June 24, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28704380/molecular-investigation-by-whole-exome-sequencing-revealed-a-high-proportion-of-pathogenic-variants-among-thai-victims-of-sudden-unexpected-death-syndrome
#3
Bhoom Suktitipat, Sakda Sathirareuangchai, Ekkapong Roothumnong, Wanna Thongnoppakhun, Purin Wangkiratikant, Nutchavadee Vorasan, Rungroj Krittayaphong, Manop Pithukpakorn, Warangkna Boonyapisit
INTRODUCTION: Sudden unexpected death syndrome (SUDS) is an important cause of death in young healthy adults with a high incident rate in Southeast Asia; however, there are no molecular autopsy reports about these victims. We performed a combination of both a detailed autopsy and a molecular autopsy by whole exome sequencing (WES) to investigate the cause of SUDS in Thai sudden death victims. MATERIALS AND METHODS: A detailed forensic autopsy was performed to identify the cause of death, followed by a molecular autopsy, in 42 sudden death victims who died between January 2015 and August 2015...
2017: PloS One
https://www.readbyqxmd.com/read/28679688/compound-heterozygous-alterations-in-intraflagellar-transport-protein-cluap1-in-a-child-with-a-novel-joubert-and-oral-facial-digital-overlap-syndrome
#4
Jennifer J Johnston, Chanjae Lee, Ingrid M Wentzensen, Melissa A Parisi, Molly M Crenshaw, Julie C Sapp, Jeffrey M Gross, John B Wallingford, Leslie G Biesecker
Disruption of normal ciliary function results in a range of diseases collectively referred to as ciliopathies. Here we report a child with a phenotype that overlapped with Joubert, oral-facial-digital, and Pallister-Hall syndromes including brain, limb, and craniofacial anomalies. We performed exome-sequence analysis on a proband and both parents, filtered for putative causative variants, and Sanger-verified variants of interest. Identified variants in CLUAP1 were functionally analyzed in a Xenopus system to determine their effect on ciliary function...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28663758/lmna-sequences-of-60-706-unrelated-individuals-reveal-132-novel-missense-variants-in-a-type-lamins-and-suggest-a-link-between-variant-p-g602s-and-type-2-diabetes
#5
Alyssa Florwick, Tejas Dharmaraj, Julie Jurgens, David Valle, Katherine L Wilson
Mutations in LMNA, encoding nuclear intermediate filament proteins lamins A and C, cause multiple diseases ('laminopathies') including muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy (FPLD2), insulin resistance syndrome and progeria. To assess the prevalence of LMNA missense mutations ('variants') in a broad, ethnically diverse population, we compared missense alleles found among 60,706 unrelated individuals in the ExAC cohort to those identified in 1,404 individuals in the laminopathy database (UMD-LMNA)...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28655895/korean-variant-archive-kova-a-reference-database-of-genetic-variations-in-the-korean-population
#6
Sangmoon Lee, Jihae Seo, Jinman Park, Jae-Yong Nam, Ahyoung Choi, Jason S Ignatius, Robert D Bjornson, Jong-Hee Chae, In-Jin Jang, Sanghyuk Lee, Woong-Yang Park, Daehyun Baek, Murim Choi
Despite efforts to interrogate human genome variation through large-scale databases, systematic preference toward populations of Caucasian descendants has resulted in unintended reduction of power in studying non-Caucasians. Here we report a compilation of coding variants from 1,055 healthy Korean individuals (KOVA; Korean Variant Archive). The samples were sequenced to a mean depth of 75x, yielding 101 singleton variants per individual. Population genetics analysis demonstrates that the Korean population is a distinct ethnic group comparable to other discrete ethnic groups in Africa and Europe, providing a rationale for such independent genomic datasets...
June 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28630944/clinvar-data-parsing
#7
Xiaolei Zhang, Eric V Minikel, Anne H O'Donnell-Luria, Daniel G MacArthur, James S Ware, Ben Weisburd
This software repository provides a pipeline for converting raw ClinVar data files into analysis-friendly tab-delimited tables, and also provides these tables for the most recent ClinVar release. Separate tables are generated for genome builds GRCh37 and GRCh38 as well as for mono-allelic variants and complex multi-allelic variants. Additionally, the tables are augmented with allele frequencies from the ExAC and gnomAD datasets as these are often consulted when analyzing ClinVar variants. Overall, this work provides ClinVar data in a format that is easier to work with and can be directly loaded into a variety of popular analysis tools such as R, python pandas, and SQL databases...
2017: Wellcome Open Research
https://www.readbyqxmd.com/read/28622062/novel-zinc-finger-protein-gene-469-znf469-variants-in-advanced-keratoconus
#8
Elvin Yildiz, Handan Bardak, Murat Gunay, Yavuz Bardak, Serhat Imamoglu, Halil Ozbas, Ozkan Bagci
PURPOSE: Common polymorphic variants upstream of Zinc finger protein gene 469 (ZNF469) have been associated with central corneal thickness. Rare ZNF469 variants have been shown in keratoconus patients. The aim of the current study was to investigate the frequency of ZNF 469 gene variants in rapidly progressive advance keratoconus patients who underwent corneal transplant surgery by the age of 30, compared to their frequency in the normal Turkish population. METHODS: A search in a patient database was performed to identify patients with a rapidly progressive keratoconus requiring corneal transplant surgery by the age of 30 in at least one eye...
June 16, 2017: Current Eye Research
https://www.readbyqxmd.com/read/28606303/effects-of-myosin-variants-on-interacting-heads-motif-explain-distinct-hypertrophic-and-dilated-cardiomyopathy-phenotypes
#9
Lorenzo Alamo, James S Ware, Antonio Pinto, Richard E Gillilan, Jonathan G Seidman, Christine E Seidman, Raúl Padrón
Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls...
June 13, 2017: ELife
https://www.readbyqxmd.com/read/28597365/a-novel-pathogenic-frameshift-variant-of-cd3e-gene-in-two-t-b-nk-scid-patients-from-turkey
#10
Sinem Firtina, Yuk Yin Ng, Ozden Hatirnaz Ng, Serdar Nepesov, Osman Yesilbas, Meltem Kilercik, Nihan Burtecene, Suzan Cinar, Yildiz Camcioglu, Ugur Ozbek, Muge Sayitoglu
Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene...
June 9, 2017: Immunogenetics
https://www.readbyqxmd.com/read/28578331/whole-genome-sequence-identified-a-rare-homozygous-pathogenic-mutation-of-the-dsg2-gene-in-a-familial-arrhythmogenic-cardiomyopathy-involving-both-ventricles
#11
Yubi Lin, Qianhuan Zhang, Zhi An Zhong, Zhe Xu, Siqi He, Fang Rao, Yang Liu, Jiaojiao Tang, Feng Wang, Hui Liu, Jiajun Xie, Hongmei Wu, Shuxia Wang, Xin Li, Zhixin Shan, Chunyu Deng, Zili Liao, Hai Deng, Hongtao Liao, Yumei Xue, Wanqun Chen, Xianzhang Zhan, Bin Zhang, Shulin Wu
BACKGROUND: This study was designed to identify the pathogenic mutation in a Chinese family with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using whole genome sequencing (WGS). METHODS AND RESULTS: Probands II:1 and II:2 underwent routine examinations for diagnosis. Genomic DNA was extracted from the peripheral blood of family members and analyzed using WGS. A total of 60,285 single-nucleotide polymorphisms (SNP) and 13,918 insertions/deletions (InDel) occurring in the exonic regions of genes and predisposing to cardiomyopathies and arrhythmias were identified...
June 3, 2017: Cardiology
https://www.readbyqxmd.com/read/28577616/dnah1-gene-mutations-and-their-potential-association-with-dysplasia-of-the-sperm-fibrous-sheath-and-infertility-in-the-han-chinese-population
#12
Yanwei Sha, Xiaoyu Yang, Libin Mei, Zhiyong Ji, Xu Wang, Lu Ding, Ping Li, Shenmin Yang
OBJECTIVE: To investigate dynein, axonemal, heavy chain 1 (DNAH1) gene mutations that may be associated with dysplasia of the sperm fibrous sheath (DFS) and infertility in the Han Chinese population. DESIGN: Dysfunction of DNAH1 is known to cause multiple morphologic abnormalities of the flagella (MMAF), DFS, and infertility. Whole-exome sequencing was performed in DFS subjects and the healthy control subjects. SETTING: Not applicable. PATIENT(S): Twenty-one patients of Han ethnicity with primary infertility and diagnosed with asthenozoospermia and MMAF, but without primary ciliary dyskinesia...
June 2017: Fertility and Sterility
https://www.readbyqxmd.com/read/28546535/a-novel-prkag2-mutation-in-a-chinese-family-with-cardiac-hypertrophy-and-ventricular-pre-excitation
#13
Kun-Qi Yang, Chao-Xia Lu, Ying Zhang, Yan-Kun Yang, Jia-Cheng Li, Tian Lan, Xu Meng, Peng Fan, Tao Tian, Lin-Ping Wang, Ya-Xin Liu, Xue Zhang, Xian-Liang Zhou
PRKAG2 syndrome is a rare autosomal dominant inherited disorder that is characterized by cardiac hypertrophy, ventricular pre-excitation and conduction system abnormalities. There is little knowledge in cardiovascular magnetic resonance (CMR) characteristics of PRKAG2 cardiomyopathy. This study investigated the genetic defect in a three-generation Chinese family with cardiac hypertrophy and ventricular pre-excitation using whole-exome sequencing. A novel missense mutation, c.1006 G > T (p.V336L), was identified in PRKAG2...
May 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28537274/characterization-of-pathogenic-sorl1-genetic-variants-for-association-with-alzheimer-s-disease-a-clinical-interpretation-strategy
#14
Henne Holstege, Sven J van der Lee, Marc Hulsman, Tsz Hang Wong, Jeroen Gj van Rooij, Marjan Weiss, Eva Louwersheimer, Frank J Wolters, Najaf Amin, André G Uitterlinden, Albert Hofman, M Arfan Ikram, John C van Swieten, Hanne Meijers-Heijboer, Wiesje M van der Flier, Marcel Jt Reinders, Cornelia M van Duijn, Philip Scheltens
Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign...
August 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28518168/using-high-resolution-variant-frequencies-to-empower-clinical-genome-interpretation
#15
Nicola Whiffin, Eric Minikel, Roddy Walsh, Anne H O'Donnell-Luria, Konrad Karczewski, Alexander Y Ing, Paul J R Barton, Birgit Funke, Stuart A Cook, Daniel MacArthur, James S Ware
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants...
May 18, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28512196/the-developmental-biology-of-genetic-notch-disorders
#16
REVIEW
Jan Mašek, Emma R Andersson
Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome...
May 15, 2017: Development
https://www.readbyqxmd.com/read/28505210/whole-exome-sequencing-of-a-consanguineous-family-identifies-the-possible-modifying-effect-of-a-globally-rare-ak5-allelic-variant-in-celiac-disease-development-among-saudi-patients
#17
Jumana Yousuf Al-Aama, Noor Ahmad Shaik, Babajan Banaganapalli, Mohammed A Salama, Omran Rashidi, Ahmed N Sahly, Mohammed O Mohsen, Harbi A Shawoosh, Hebah Ahmad Shalabi, Mohammad Al Edreesi, Sameer E Alharthi, Jun Wang, Ramu Elango, Omar I Saadah
Celiac disease (CD), a multi-factorial auto-inflammatory disease of the small intestine, is known to occur in both sporadic and familial forms. Together HLA and Non-HLA genes can explain up to 50% of CD's heritability. In order to discover the missing heritability due to rare variants, we have exome sequenced a consanguineous Saudi family presenting CD in an autosomal recessive (AR) pattern. We have identified a rare homozygous insertion c.1683_1684insATT, in the conserved coding region of AK5 gene that showed classical AR model segregation in this family...
2017: PloS One
https://www.readbyqxmd.com/read/28502612/marrvel-integration-of-human-and-model-organism-genetic-resources-to-facilitate-functional-annotation-of-the-human-genome
#18
Julia Wang, Rami Al-Ouran, Yanhui Hu, Seon-Young Kim, Ying-Wooi Wan, Michael F Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, Aram Comjean, Stephanie E Mohr, Norbert Perrimon, Zhandong Liu, Hugo J Bellen
One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format...
June 1, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28487536/common-sequence-variants-affect-molecular-function-more-than-rare-variants
#19
Yannick Mahlich, Jonas Reeb, Maximilian Hecht, Maria Schelling, Tjaart Andries Petrus De Beer, Yana Bromberg, Burkhard Rost
Any two unrelated individuals differ by about 10,000 single amino acid variants (SAVs). Do these impact molecular function? Experimental answers cannot answer comprehensively, while state-of-the-art prediction methods can. We predicted the functional impacts of SAVs within human and for variants between human and other species. Several surprising results stood out. Firstly, four methods (CADD, PolyPhen-2, SIFT, and SNAP2) agreed within 10 percentage points on the percentage of rare SAVs predicted with effect...
May 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28471432/assessment-of-the-exac-data-set-for-the-presence-of-individuals-with-pathogenic-genotypes-implicated-in-severe-mendelian-pediatric-disorders
#20
Maja Tarailo-Graovac, Jing Yun Alice Zhu, Allison Matthews, Clara D M van Karnebeek, Wyeth W Wasserman
PurposeWe analyzed the Exome Aggregation Consortium (ExAC) data set for the presence of individuals with pathogenic genotypes implicated in Mendelian pediatric disorders.MethodsClinVar likely/pathogenic variants supported by at least one peer-reviewed publication were assessed within the ExAC database to identify individuals expected to exhibit a childhood disorder based on concordance with disease inheritance modes: heterozygous (for dominant), homozygous (for recessive) or hemizygous (for X-linked recessive conditions)...
May 4, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
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