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exom sequencing

Leonela N Luce, Micaela Carcione, Chiara Mazzanti, Marcela Ferrer, Irene Szijan, Florencia Giliberto
Dystrophinopathies are neuromuscular X-linked recessive diseases caused by mutations in the DMD gene. This study aimed to identify DMD gene small mutations by Whole Exome Sequencing (WES), in order to confirm clinical diagnosis, identify candidates for Ataluren treatment and perform carrier status testing. Furthermore, was our goal to characterize the DMD sequence variants and identify ancestral haplotypes. We analyzed 40 non-related individuals (38 affected boys with dystrophinopathy presumptive clinical diagnosis and 2 at-risk women) with negative MLPA results...
September 6, 2018: Neuromuscular Disorders: NMD
Velina Kozareva, Clayton Stroff, Maxwell Silver, Jonathan F Freidin, Nigel F Delaney
BACKGROUND: Detection of copy number variants (CNVs) is an important aspect of clinical testing for several disorders, including Duchenne muscular dystrophy, and is often performed using multiplex ligation-dependent probe amplification (MLPA). However, since many genetic carrier screens depend instead on next-generation sequencing (NGS) for wider discovery of small variants, they often do not include CNV analysis. Moreover, most computational techniques developed to detect CNVs from exome sequencing data are not suitable for carrier screening, as they require matched normals, very large cohorts, or extensive gene panels...
October 20, 2018: BMC Medical Genomics
Aaron Hamvas, Rui Feng, Yingtao Bi, Fan Wang, Soumyaroop Bhattacharya, Jared Mereness, Madhurima Kaushal, C Michael Cotten, Philip L Ballard, Thomas J Mariani
BACKGROUND: Previous studies have identified genetic variants associated with bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, findings with genome-wide significance have been rare, and not replicated. We hypothesized that whole exome sequencing (WES) of premature subjects with extremely divergent phenotypic outcomes could facilitate the identification of genetic variants or gene networks contributing disease risk. RESULTS: The Prematurity and Respiratory Outcomes Program (PROP) recruited a cohort of > 765 extremely preterm infants for the identification of markers of respiratory morbidity...
October 20, 2018: BMC Genetics
Wenxia Zheng, Zhenxing Yan, Rongni He, Yaowei Huang, Aiqun Lin, Wei Huang, Yuying Su, Shaoyuan Li, Victor Wei Zhang, Huifang Xie
BACKGROUND: DNA methyltransferase 1 (EC, encoded by DNMT1 gene, is one of key enzymes in maintaining DNA methylation patterns of the human genome. It plays a crucial role in embryonic development, imprinting and genome stability, cell differentiation. The dysfunction of this group of enzymes can lead to a variety of human genetic disorders. Until now, mutations in DNMT1 have been found to be associated with two distinct phenotypes. Mutations in exon 20 of this gene leads to hereditary sensory and autonomic neuropathy type IE, and mutations in exon 21 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy...
October 20, 2018: BMC Neurology
Yuko Omori, Yusuke Ono, Mishie Tanino, Hidenori Karasaki, Hiroshi Yamaguchi, Toru Furukawa, Katsuro Enomoto, Jun Ueda, Atsuko Sumi, Jin Katayama, Miho Muraki, Kenzui Taniue, Kuniyuki Takahashi, Yoshiyasu Ambo, Toshiya Shinohara, Hiroshi Nishihara, Junpei Sasajima, Hiroyuki Maguchi, Yusuke Mizukami, Toshikatsu Okumura, Shinya Tanaka
BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about mechanism of progression. This makes it a challenge to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs; 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors...
October 17, 2018: Gastroenterology
Mariateresa Di Stazio, Chiara Collesi, Diego Vozzi, Wei Liu, Mike Myers, Anna Morgan, Pio Adamo D Adamo, Giorgia Girotto, Elisa Rubinato, Mauro Giacca, Paolo Gasparini
Hereditary hearing loss (HHL) is an extremely heterogeneous disorder with autosomal dominant, recessive, and X-linked forms. Here, we described an Italian pedigree affected by HHL but also prostate hyperplasia and increased ratio of the free/total PSA levels, with the unusual and extremely rare Y-linked pattern of inheritance. Using exome sequencing we found a missense variant (r.206A>T leading to p.Asp69Val) in the TBL1Y gene. TBL1Y is homologous of TBL1X, whose partial deletion has described to be involved in X-linked hearing loss...
October 19, 2018: European Journal of Human Genetics: EJHG
Chiara Magri, Edoardo Giacopuzzi, Luca La Via, Daniela Bonini, Viola Ravasio, Mohammed E A Elhussiny, Flavia Orizio, Fabrizio Gangemi, Paolo Valsecchi, Roberto Bresciani, Alessandro Barbon, Antonio Vita, Massimo Gennarelli
Recently, by whole exome sequencing of schizophrenia (SCZ) patients, we identified a subject that was homozygous for a novel missense substitution (c.391 A > G) in the glutamate acid decarboxylase 1 (GAD1) gene. GAD1 encodes for GAD67 enzyme, catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Here, we studied the impact of this mutation on GAD67 activity, dimerization and subcellular localization. Biochemical assay revealed that c.391 A > G reduces GAD67 enzymatic activity by ~30%, probably due to the impaired homodimerization of homozygous mutants as highlighted by proximity ligation assays...
October 19, 2018: Scientific Reports
Myriam Vezain, Matthieu Lecuyer, Marina Rubio, Valérie Dupé, Leslie Ratié, Véronique David, Laurent Pasquier, Sylvie Odent, Sophie Coutant, Isabelle Tournier, Laetitia Trestard, Homa Adle-Biassette, Denis Vivien, Thierry Frébourg, Bruno J Gonzalez, Annie Laquerrière, Pascale Saugier-Veber
Extreme microcephaly and rhombencephalosynapsis represent unusual pathological conditions, each of which occurs in isolation or in association with various other cerebral and or extracerebral anomalies. Unlike microcephaly for which several disease-causing genes have been identified with different modes of inheritance, the molecular bases of rhombencephalosynapsis remain unknown and rhombencephalosynapsis presents mainly as a sporadic condition consistent with de novo dominant variations. We report for the first time the association of extreme microcephaly with almost no sulcation and rhombencephalosynapsis in a fœtus for which comparative patient-parent exome sequencing strategy revealed a heterozygous de novo missense variant in the ADGRL2 gene...
October 19, 2018: Acta Neuropathologica Communications
Ke Liang, Jun Wang, Yan Wang, Zhiqiang Zhou, Shuang Ge, Shuyu Mei, Hailing Li, Xiaotong Jing, Cuijuan Zhang
Classical Hodgkin lymphoma (cHL) and ALK-anaplastic large cell lymphoma (ALCL) share many morphological and immunohistochemical features, causing difficulties in differential diagnosis. Aberrant T-cell/B-cell antigen (TCA/BCA) expression in cHL/ALCL has previously been reported, but differences in the broader morphological and genetic features still remain unclear. We first explored the histological and immunohistochemical characteristics of cHL and ALCL with or without aberrant expression. Out of 68 cHL cases, 10 (14...
October 16, 2018: Human Pathology
Hong Pan, Huifen Xiang, Jing Wang, Zhaolian Wei, Yiran Zhou, Beihong Liu, Tengyan Li, Xu Ma, Yunxia Cao, Binbin Wang
Recurrent pregnancy loss (RPL) is a major concern for women's reproductive health. Several studies have proven that genetics is a major factor leading to unexplained RPL, but the maternal pathogenic genes involved in RPL remain largely unknown. A consanguineous family, including the parents who were cousins and their three daughters who had been diagnosed as non-syndromic unexplained RPL were recruited in this study. A rare homozygous variant in Calcyphosine (CAPS) (ENST00000588776: c.377delC, p.Leu127Trpfs) might be the potential candidate variant for this RPL family through whole-exome sequencing...
October 16, 2018: American Journal of Pathology
Ryo Tamura, Hirofumi Nakaoka, Kosuke Yoshihara, Yutaro Mori, Nozomi Yachida, Nobumichi Nishikawa, Teiichi Motoyama, Shujiro Okuda, Ituro Inoue, Takayuki Enomoto
Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in-frame fusion transcripts: MXD4-NUTM1 and ARL6-POT1...
November 2018: Genes, Chromosomes & Cancer
Richard G Lee, Maryam Sedghi, Mehri Salari, Anne-Marie J Shearwood, Maike Stentenbach, Ariana Kariminejad, Hayley Goullee, Oliver Rackham, Nigel G Laing, Homa Tajsharghi, Aleksandra Filipovska
Objective: Our goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation. Methods: We combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation. Results: Here, we report an association of a homozygous variant in CHCHD2 , encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman...
October 2018: Neurology. Genetics
Malavika Hebbar, Anju Shukla, Sheela Nampoothiri, Stephanie Bielas, Katta M Girisha
Hereditary spastic paraplegias are a group of genetically heterogeneous neurological disorders characterized by progressive weakness and spasticity of lower limbs. We ascertained five families with eight individuals with hereditary spastic paraplegia. Pathogenic variants were identified by exome sequencing of index cases. The cohort consists of three families with spastic paraplegia type 47 (AP4B1) with a common mutation in two families, a family with spastic paraplegia type 50 (AP4M1), and two male siblings with X-linked spastic paraplegia 2 (PLP1)...
October 18, 2018: Journal of Human Genetics
Chelisa Cardinez, Bahar Miraghazadeh, Kay Tanita, Elizabeth da Silva, Akihiro Hoshino, Satoshi Okada, Rochna Chand, Takaki Asano, Miyuki Tsumura, Kenichi Yoshida, Hidenori Ohnishi, Zenichiro Kato, Masahide Yamazaki, Yusuke Okuno, Satoru Miyano, Seiji Kojima, Seishi Ogawa, T Daniel Andrews, Matthew A Field, Gaetan Burgio, Tomohiro Morio, Carola G Vinuesa, Hirokazu Kanegane, Matthew C Cook
Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo IKBKB missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. IKBKB encodes IKK2, which activates NF-κB signaling...
October 18, 2018: Journal of Experimental Medicine
Prabhakar S Kedar, Vinod Gupta, Rashmi Dongerdiye, Ashish Chiddarwar, Prashant Warang, Manisha R Madkaikar
Glucose-6-phosphate isomerase (GPI) deficiency is an autosomal recessive genetic disorder causing congenital haemolytic anaemia (CHA). Diagnosis of GPI deficiency by the biochemical method is unpredicted. Molecular diagnosis by identifying genetic mutation is the gold standard method for confirmation of disease, but causative genes involved in CHA are numerous, and identifying a gene-by-gene approach using Sanger sequencing is also cumbersome, expensive and labour intensive. Recently, next-generation targeted sequencing is more useful in the diagnosis of unexplained haemolytic anaemia...
October 18, 2018: Journal of Clinical Pathology
Filippo Manti, Francesca Nardecchia, Sabina Barresi, Martina Venditti, Simone Pizzi, Fadi F Hamdan, Nenad Blau, Alberto Burlina, Marco Tartaglia, Vincenzo Leuzzi
INTRODUCTION: Clathrins play a key role in endocytosis, recycling, and trafficking as well as the generation of presynaptic vesicles. We report a new clinical condition associated with a de novo variant in the CLTC gene, which encodes the clathrin heavy polypeptide. CASE REPORT: This 30-year-old woman presented with a developmental disorder during childhood that progressed to mild cognitive decline in late childhood and relapsing-remitting hypokinetic-rigid syndrome with severe achalasia, weight loss, and mood disorder in adulthood...
October 11, 2018: Parkinsonism & related Disorders
Elaine Guo Yan Chew, Herty Liany, Louis C S Tan, Wing-Lok Au, Kumar-M Prakash, Azlina Ahmad Annuar, Anne Y Y Chan, Shen-Yang Lim, Vincent Mok, Sun Ju Chung, Kyuyoung Song, Jianjun Liu, Jia Nee Foo, Eng-King Tan
Recent whole-exome sequencing studies in European patients with Parkinson's disease (PD) have identified potential risk variants across 33 novel PD candidate genes. We aim to determine if these reported candidate genes are similarly implicated in Asians by assessing common, rare, and novel nonsynonymous coding variants by sequencing all 33 genes in 198 Chinese samples and genotyping coding variants in an independent set of 9756 Chinese samples. We carried out further targeted sequencing of CD36 in an additional 576 Chinese and Korean samples...
September 21, 2018: Neurobiology of Aging
Byung Dae Lee, Ja Young Kong, Chae Hwa Kwon, Je Min Park, Young Min Lee, Eunsoo Moon, Hee Jeong Jeong, Soo Yeon Kim, Kang Yoon Lee, Hwagyu Suh
Idiopathic basal ganglia calcification (IBGC) is characterized by brain calcification and a wide variety of neurological and psychiatric symptoms. In families displaying an autosomal dominant inheritance pattern, three causative genes have been identified: SLC20A2, PDGFRB, and very recently, PDGFB. While in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrences are rare. We report a case of a 61-year-old woman who presented with depressive and dystonic symptoms revealing IBGC...
October 2018: Medicine (Baltimore)
Przemyslaw W Twardowski, Catherine M Tangen, Xiwei Wu, Melissa R Plets, Elizabeth R Plimack, Neeraj Agarwal, Nicholas J Vogelzang, Jinhui Wang, Shu Tao, Ian M Thompson, Primo Lara
Background: Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway. A randomized multicenter parallel two-stage phase II trial of MET inhibitor tivantinib alone or in combination with EGFR inhibitor erlotinib was conducted in patients with pRCC. Methods: Patients with advanced pRCC and 0-1 prior systemic therapy were randomly assigned to tivantinib 360 mg BID (Arm 1) or tivantinib 360 mg BID plus erlotinib 150 mg daily (Arm 2)...
November 27, 2017: Kidney cancer
Jeffrey W Tyner, Cristina E Tognon, Daniel Bottomly, Beth Wilmot, Stephen E Kurtz, Samantha L Savage, Nicola Long, Anna Reister Schultz, Elie Traer, Melissa Abel, Anupriya Agarwal, Aurora Blucher, Uma Borate, Jade Bryant, Russell Burke, Amy Carlos, Richie Carpenter, Joseph Carroll, Bill H Chang, Cody Coblentz, Amanda d'Almeida, Rachel Cook, Alexey Danilov, Kim-Hien T Dao, Michie Degnin, Deirdre Devine, James Dibb, David K Edwards, Christopher A Eide, Isabel English, Jason Glover, Rachel Henson, Hibery Ho, Abdusebur Jemal, Kara Johnson, Ryan Johnson, Brian Junio, Andy Kaempf, Jessica Leonard, Chenwei Lin, Selina Qiuying Liu, Pierrette Lo, Marc M Loriaux, Samuel Luty, Tara Macey, Jason MacManiman, Jacqueline Martinez, Motomi Mori, Dylan Nelson, Ceilidh Nichols, Jill Peters, Justin Ramsdill, Angela Rofelty, Robert Schuff, Robert Searles, Erik Segerdell, Rebecca L Smith, Stephen E Spurgeon, Tyler Sweeney, Aashis Thapa, Corinne Visser, Jake Wagner, Kevin Watanabe-Smith, Kristen Werth, Joelle Wolf, Libbey White, Amy Yates, Haijiao Zhang, Christopher R Cogle, Robert H Collins, Denise C Connolly, Michael W Deininger, Leylah Drusbosky, Christopher S Hourigan, Craig T Jordan, Patricia Kropf, Tara L Lin, Micaela E Martinez, Bruno C Medeiros, Rachel R Pallapati, Daniel A Pollyea, Ronan T Swords, Justin M Watts, Scott J Weir, David L Wiest, Ryan M Winters, Shannon K McWeeney, Brian J Druker
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML...
October 17, 2018: Nature
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