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exom sequencing

Florence Koeppel, Alexandre Bobard, Céline Lefebvre, Marion Pedrero, Marc Deloger, Yannick Boursin, Catherine Richon, Romy Chen-Min-Tao, Guillaume Robert, Guillaume Meurice, Etienne Rouleau, Stefan Michiels, Christophe Massard, Jean-Yves Scoazec, Eric Solary, Jean-Charles Soria, Fabrice André, Ludovic Lacroix
Comprehensive genomic profiling using high-throughput sequencing brings a wealth of information, and its place in the clinical setting has been increasingly prominent. This review emphasizes the utility of whole-exome sequencing (WES) and transcriptome sequencing (RNAseq) in patient care and clinical research, based on published reports as well as our experience with the MOSCATO-01 (MOlecular Screening for CAncer Treatment Optimization) molecular triage trial at Gustave Roussy Cancer Center. In this trial, all contributive samples of patients with advanced solid tumors were analyzed prospectively with targeted gene sequencing (TGS) and comparative genomic hybridization...
July 2018: Cancer Journal
Michael Ta, Changchuan Yin, Gary Lee Smith, Wenbo Xu
Multiplexed molecular barcoded amplicon sequencing has been previously demonstrated to improve the sensitivity of low-frequency variant detection. Molecular barcoded reads can be used to identify and correct amplification biases introduced during library preparation and sequencing errors. We propose a generic workflow to improve variant calling accuracy that takes advantage of molecular barcoded sequencing reads by applying a base score correction method to duplicate or overlapping read pairs across the targeted panel...
August 17, 2018: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
Vincent Jonchere, Laetitia Marisa, Malorie Greene, Alain Virouleau, Olivier Buhard, Romane Bertrand, Magali Svrcek, Pascale Cervera, Anastasia Goloudina, Erell Guillerm, Florence Coulet, Samuel Landman, Toky Ratovomanana, Sylvie Job, Mira Ayadi, Nabila Elarouci, Lucile Armenoult, Fatiha Merabtene, Sylvie Dumont, Yann Parc, Jérémie H Lefèvre, Thierry André, Jean-François Fléjou, Agathe Guilloux, Ada Collura, Aurélien de Reyniès, Alex Duval
Background & Aims: Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study...
2018: Cellular and Molecular Gastroenterology and Hepatology
Robert A Sisk, Robert B Hufnagel, Ailee Laham, Elizabeth S Wohler, Nara Sobreira, Zubair M Ahmed
Purpose: To present new clinical features, multimodal and ultrawide-field imaging characteristics of peripheral cone dystrophy (PCD), and results of laboratory and genetic investigation to decipher the etiology. Methods: Retrospective observational case-series. Results: Three patients with PCD presented with bilateral paracentral scotomas and a mean visual acuity of 20/25. All exhibited confluent macular hyperautofluorescence with a central bull's eye lesion...
2018: Journal of Ophthalmology
Jordi Corominas, Marieke Klein, Tetyana Zayats, Olga Rivero, Georg C Ziegler, Marc Pauper, Kornelia Neveling, Geert Poelmans, Charline Jansch, Evgeniy Svirin, Julia Geissler, Heike Weber, Andreas Reif, Alejandro Arias Vasquez, Tessel E Galesloot, Lambertus A L M Kiemeney, Jan K Buitelaar, Josep-Antoni Ramos-Quiroga, Bru Cormand, Marta Ribasés, Kristian Hveem, Maiken Elvestad Gabrielsen, Per Hoffmann, Sven Cichon, Jan Haavik, Stefan Johansson, Christian P Jacob, Marcel Romanos, Barbara Franke, Klaus-Peter Lesch
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (Ntotal  = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those...
August 16, 2018: Molecular Psychiatry
Kun Wang, Sen Zhao, Qianqian Zhang, Jian Yuan, Jiaqi Liu, Xinghuan Ding, Xiaofei Song, Jiachen Lin, Renqian Du, Yangzhong Zhou, Michihiko Sugimoto, Weisheng Chen, Bo Yuan, Jian Liu, Zihui Yan, Bowen Liu, Yisen Zhang, Xiaoxin Li, Yuchen Niu, Bo Long, Yiping Shen, Shuyang Zhang, Kuniya Abe, Jianzhong Su, Zhihong Wu, Nan Wu, Pengfei Liu, Xinjian Yang
Intracranial vertebral-basilar artery dissection (IVAD) is an arterial disorder leading to life-threatening consequences. Genetic factors are known to be causative to certain syndromic forms of IVAD. However, systematic study of the molecular basis of sporadic and isolated IVAD is lacking. To identify genetic variants contributing to the etiology of IVAD, we enrolled a cohort of 44 unrelated cases with a clinical diagnosis of isolated IVAD and performed whole-exome sequencing (WES) for all the participants; a trio exome sequencing approach was used when samples from both parents were available...
August 16, 2018: Journal of Human Genetics
Luca Trotta, Anna Norberg, Mervi Taskinen, Vivien Béziat, Sofie Degerman, Ulla Wartiovaara-Kautto, Hannamari Välimaa, Kirsi Jahnukainen, Jean-Laurent Casanova, Mikko Seppänen, Janna Saarela, Minna Koskenvuo, Timi Martelius
BACKGROUND: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs...
August 17, 2018: Orphanet Journal of Rare Diseases
Reka Kovacs-Nagy, Gilles Morin, Maria Al Nouri, Oliver Brandau, Nebal Waill Saadi, Mohammed A Nouri, Florence van den Broek, Holger Prokisch, Johannes A Mayr, Saskia B Wortmann
Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ , SERAC1 , OPA3 , CLPB , DNAJC19 , TMEM70 , TIMM50 )...
August 16, 2018: Neuropediatrics
Soon-Chan Kim, Chang-Won Hong, Sang-Geun Jang, Ye-Ah Kim, Byong-Chul Yoo, Young-Kyoung Shin, Seung-Yong Jeong, Ja-Lok Ku, Jae-Gahb Park
Peritoneal metastasis is one of the major patterns of unresectability in colorectal cancer (CRC) and a cause of death in advanced CRC. Identification of distinct gene expressions between primary CRC and peritoneal seeding metastasis is to predict the metastatic potential of primary human CRC. Three pairs of primary CRC (SNU-2335A, SNU-2404A, and SNU-2414A) and corresponding peritoneal seeding (SNU-2335D, SNU-2404B, and SNU-2414B) cell lines were established to determine the different gene expressions and resulting aberrated signaling pathways in peritoneal metastasis tumor using whole exome sequencing and microarray...
August 13, 2018: Translational Oncology
Mariarosaria Lang-Muritano, Patrick Sproll, Sascha Wyss, Anne Kolly, Renate Hürlimann, Daniel Konrad, Anna Biason-Lauber
Context: Estrogen resistance due to mutations in the estrogen receptor α (ESR1) was described in men and women and is characterized by osteoporosis, delayed bone age and continuous growth in adulthood, delayed puberty and multiple ovarian cysts in women. Although mutations in ESR2 were found in 46, XY patients with differences of sex development (DSD), no genetic variants of estrogen receptor β (ESR2) were linked to gonadal defects in women. Settings and Patient: Here we describe a 16-year old woman who came to our tertiary care hospital with complete lack of estrogen action, as demonstrated by absent breast development, primary amenorrhea, and osteoporosis, resembling patients with ESR1 mutation...
August 2, 2018: Journal of Clinical Endocrinology and Metabolism
Charlotte M Chiong, Ma Rina T Reyes-Quintos, Talitha Karisse L Yarza, Celina Ann M Tobias-Grasso, Anushree Acharya, Suzanne M Leal, Karen L Mohlke, Nanette L Mayol, Eva Maria Cutiongco-de la Paz, Regie Lyn P Santos-Cortez
HYPOTHESIS: Variants in SLC26A4 are an important cause of congenital hearing impairment in the Philippines. BACKGROUND: Cochlear implantation is a standard rehabilitation option for congenital hearing impairment worldwide, but places a huge cost burden in lower-income countries. The study of risk factors such as genetic variants that may help determine genetic etiology of hearing loss and also predict cochlear implant outcomes is therefore beneficial. METHODS: DNA samples from 29 GJB2-negative Filipino cochlear implantees were Sanger-sequenced for the coding exons of SLC26A4...
September 2018: Otology & Neurotology
Priyanka Nandakumar, Alanna C Morrison, Megan L Grove, Eric Boerwinkle, Aravinda Chakravarti
Rare variants, in particular renal salt handling genes, contribute to monogenic forms of hypertension and hypotension syndromes with electrolyte abnormalities. A study by Ji et al (2008) demonstrated this effect for rare loss-of-function coding variants in SLC12A3 (NCCT), SLC12A1 (NKCC2), and KCNJ1 (ROMK) that led to reduction of ∼6 mm Hg for SBP and ∼3 mm Hg for DBP among carriers in 2492 European ancestry Framingham Heart Study (FHS) subjects. These findings support a potentially large role for these variants in interindividual variation in systolic and diastolic blood pressure (SBP, DBP) in the population...
August 2018: Medicine (Baltimore)
Baotian Wang, De Wu, Jiulai Tang
Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder. Phospholipase A2 group VI (PLA2G6) gene mutations have been identified in the majority of individuals with INAD. The present case report is on a Chinese female pediatric patient (age, 18 months) diagnosed with INAD with deafness. To date, only four cases of INAD with hearing loss have been reported, PLA2G6-association has not been investigated. Next-generation DNA sequencing technology was used to identify disease-associated genes and Sanger sequencing was applied to verify the mutation in the patient's pedigree...
August 2018: Experimental and Therapeutic Medicine
Davide Tonduti, Celeste Panteghini, Anna Pichiecchio, Alice Decio, Miryam Carecchio, Chiara Reale, Isabella Moroni, Nardo Nardocci, Jaume Campistol, Angela Garcia-Cazorla, Belen Perez Duenas, Luisa Chiapparini, Barbara Garavaglia, Simona Orcesi
BACKGROUND: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. METHODS: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. RESULTS: We collected a series of fifty patients...
August 16, 2018: Orphanet Journal of Rare Diseases
Liang-Liang Fan, Ya-Qin Chen, Hao Huang, Jie-Yuan Jin, Jing-Jing Li, Zhi-Ping Tan
BACKGROUND: Dilated Cardiomyopathy is a serious heart disorder that may induce sudden cardiac death and heart failure. Significant progress has been made in understanding the molecular basis of dilated cardiomyopathy. In previous studies, mutations in more than fifty genes have been identified in dilated cardiomyopathy patients. The purpose of this study was to detect the genetic lesion in a family from the central south of China affected by severe dilated cardiomyopathy. METHODS: Whole-exome sequencing combined with cardiomyopathy-related genes list were used to analyse the mutations of the proband...
August 15, 2018: Cardiology in the Young
Qingwen Zhu, Yufei Ni, Jing Wang, Honggang Yin, Qin Zhang, Lingli Zhang, Wenjun Bian, Bo Liang, Lingyin Kong, Liming Xuan, Naru Lu
Cerebral palsy (CP) is a non-progressive neurological disease, of which susceptibility is linked to genetic and environmental risk factors. More and more studies have shown that CP might be caused by multiple genetic factors, similar to other neurodevelopmental disorders. Due to the high genetic heterogeneity of CP, we focused on investigating related molecular pathways. Ten children with CP were collected for whole-exome sequencing by next-generation sequencing (NGS) technology. Customized processes were used to identify potential pathogenic pathways and variants...
August 14, 2018: Genes & Genomics
Guido Zagnoli-Vieira, Francesco Bruni, Kyle Thompson, Langping He, Sarah Walker, Arjan P M de Brouwer, Robert Taylor, Dmitriy Niyazov, Keith W Caldecott
Objective: To address the relationship between mutations in the DNA strand break repair protein tyrosyl DNA phosphodiesterase 2 (TDP2) and spinocerebellar ataxia autosomal recessive 23 (SCAR23) and to characterize the cellular phenotype of primary fibroblasts from this disease. Methods: We have used exome sequencing, Sanger sequencing, gene editing and cell biology, biochemistry, and subcellular mitochondrial analyses for this study. Results: We have identified a patient in the United States with SCAR23 harboring the same homozygous TDP2 mutation as previously reported in 3 Irish siblings (c...
August 2018: Neurology. Genetics
Betsy E P Ostrander, Russell J Butterfield, Brent S Pedersen, Andrew J Farrell, Ryan M Layer, Alistair Ward, Chase Miller, Tonya DiSera, Francis M Filloux, Meghan S Candee, Tara Newcomb, Joshua L Bonkowsky, Gabor T Marth, Aaron R Quinlan
Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE...
2018: NPJ Genomic Medicine
Christopher Cy Mak, Gordon Kc Leung, Gary Tk Mok, Kit San Yeung, Wanling Yang, Cheuk-Wing Fung, Sophelia Hs Chan, So-Lun Lee, Ni-Chung Lee, Rolph Pfundt, Yu-Lung Lau, Brian Hy Chung
Currently, offering whole-exome sequencing (WES) via collaboration with an external laboratory is increasingly common. However, the receipt of a WES report can be merely the beginning of a continuing exploration process rather than the end of the diagnostic odyssey. The laboratory often does not have the information the physician has, and any discrepancies in variant interpretation must be addressed by a medical geneticist. In this study, we performed diagnostic WES of 104 patients with paediatric-onset genetic diseases...
2018: NPJ Genomic Medicine
Adi Reches, Liran Hiersch, Sharon Simchoni, Dalit Barel, Rotem Greenberg, Liat Ben Sira, Gustavo Malinger, Yuval Yaron
OBJECTIVE: We describe our experience with whole-exome sequencing (WES) in fetuses with central nervous system (CNS) abnormalities following a normal chromosomal microarray result. METHODS: During the study period (2014-2017) 7 cases (9 fetuses) with prenatally diagnosed CNS abnormality, whose chromosomal microarray analysis was negative, were offered whole-exome sequencing analysis. RESULTS: A pathogenic or a likely pathogenic variant was found in 5 cases including a previously described, likely pathogenic de novo TUBA1A variant (Case #1); a previously described homozygous VRK1 variant (Case #2); an X-linked ARX variant (Case #3); a likely pathogenic heterozygous variant in the TUBB3 gene (Case #5)...
August 14, 2018: Journal of Perinatology: Official Journal of the California Perinatal Association
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