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Whole genome sequencing pathology

Justin O Szot, Hartmut Cuny, Gillian M Blue, David T Humphreys, Eddie Ip, Katrina Harrison, Gary F Sholler, Eleni Giannoulatou, Paul Leo, Emma L Duncan, Duncan B Sparrow, Joshua W K Ho, Robert M Graham, Nicholas Pachter, Gavin Chapman, David S Winlaw, Sally L Dunwoodie
BACKGROUND: Congenital heart disease (CHD)-structural abnormalities of the heart that arise during embryonic development-is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD. METHODS: Whole-exome sequencing was performed with the DNA of multiple family members...
March 2018: Circ Genom Precis Med
Lv Liu, Hong Luo
Primary ciliary dyskinesia (PCD) is a clinical rare peculiar disorder, mainly featured by respiratory infection, tympanitis, nasosinusitis, and male infertility. Previous study demonstrated it is an autosomal recessive disease and by 2017 almost 40 pathologic genes have been identified. Among them are the leucine-rich repeat- (LRR-) containing 6 (LRRC6) codes for a 463-amino-acid cytoplasmic protein, expressed distinctively in motile cilia cells, including the testis cells and the respiratory epithelial cells...
2018: BioMed Research International
David J Birnbaum, François Bertucci, Pascal Finetti, Daniel Birnbaum, Emilie Mamessier
Clinico-pathological factors fail to consistently predict the outcome after pancreatic resection for oancreatic ductal adenocarcinoma (PDAC). PDACs show a high level of inter and intra tumor genetic heterogeneity. A molecular classification should help reduce heterogeneity among patients, with the consequences of better predicting evolution and better orienting the treatment. This review summarizes the information that should be retained in clinical practice from all the molecular analyses. PDAC can be classified based on mutational subtypes and gene alterations...
February 27, 2018: Biochimica et Biophysica Acta
Sam Chai, Xiaoping Wan, Angelina Ramirez-Navarro, Paul J Tesar, Elizabeth S Kaufman, Eckhard Ficker, Alfred L George, Isabelle Deschênes
Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner...
February 12, 2018: Journal of Clinical Investigation
Gael D Maganga, Ingrid Labouba, Barthélémy Ngoubangoye, Andriniaina A Nkili-Meyong, Daniel Obame Ondo, Eric M Leroy, Nicolas Berthet
Canine distemper (CD) is the most deadly disease in dogs with mortality rates reaching 50%. The pathological agent, the CD virus (CDV), generally causes a severe systemic disease, although the nervous form can coexist with the acute catarrhal form in the same individual. In this study, we describe an outbreak of 18 cases of CD that occurred in 2015 in a German Shepherd dog population in northwestern Gabon. In addition, we determined the sequence of the CDV genotype associated with this fatal distemper infection in Gabon and compared it with other published CDV sequences...
January 30, 2018: Virus Research
Jan Smetana, Jan Oppelt, Martin Štork, Luděk Pour, Petr Kuglík
Background: Catastrophic chromosomal event known as chromothripsis was proven to be a significant hallmark of poor prognosis in several cancer diseases. While this phenomenon is very rare in among multiple myeloma (MM) patients, its presence in karyotype is associated with very poor prognosis. Case presentation: In our case, we report a 62 year female patient with rapid progression of multiple myeloma (MM) into extramedullary disease and short overall survival (OS = 23 months)...
2018: Molecular Cytogenetics
Daniel Koile, Marta Cordoba, Maximiliano de Sousa Serro, Marcelo Andres Kauffman, Patricio Yankilevich
BACKGROUND: GenIO is a novel web-server, designed to assist clinical genomics researchers and medical doctors in the diagnostic process of rare genetic diseases. The tool identifies the most probable variants causing a rare disease, using the genomic and clinical information provided by a medical practitioner. Variants identified in a whole-genome, whole-exome or target sequencing studies are annotated, classified and filtered by clinical significance. Candidate genes associated with the patient's symptoms, suspected disease and complementary findings are identified to obtain a small manageable number of the most probable recessive and dominant candidate gene variants associated with the rare disease case...
January 27, 2018: BMC Bioinformatics
Giorgio Tasca, Bjarne Udd
Phenotypic and genetic/allelic heterogeneity is a feature of many neuromuscular disorders, titinopathies being one of them. Hereditary Myopathy with Early Respiratory Failure (HMERF) has been considered an extremely rare disease with definite clinicopathologic hallmarks, and geographically restricted to the Northern European population with one single titin gene defect identified in previous years. The recent availability of massive parallel sequencing techniques, allowing the screening of all coding regions of the genome in undiagnosed patients, together with a growing awareness of the main muscle MRI features of the disease, has led to the discovery of a number of HMERF families and new titin mutations in the last five years...
December 12, 2017: Neuromuscular Disorders: NMD
Christopher P Wardell, Masashi Fujita, Toru Yamada, Michele Simbolo, Matteo Fassan, Rosa Karlic, Paz Polak, Jaegil Kim, Yutaka Hatanaka, Kazuhiro Maejima, Rita T Lawlor, Yoshitsugu Nakanishi, Tomoko Mitsuhashi, Akihiro Fujimoto, Mayuko Furuta, Andrea Ruzzenente, Simone Conci, Ayako Oosawa, Aya Sasaki-Oku, Kaoru Nakano, Hiroko Tanaka, Yujiro Yamamoto, Kubo Michiaki, Yoshiiku Kawakami, Hiroshi Aikata, Masaki Ueno, Shinya Hayami, Kunihito Gotoh, Shun-Ichi Ariizumi, Masakazu Yamamoto, Hiroki Yamaue, Kazuaki Chayama, Satoru Miyano, Gad Getz, Aldo Scarpa, Satoshi Hirano, Toru Nakamura, Hidewaki Nakagawa
BACKGROUND & AIMS: Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous with poor response to treatments. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape. METHODS: We analyzed 412 BTC samples from Japanese and Italian populations, with 107 whole exome sequencing (WES), 39 whole genome sequencing (WGS), and targeted sequencing of a further 266 samples...
January 19, 2018: Journal of Hepatology
Stefania Bellone, Natalia Buza, Jungmin Choi, Luca Zammataro, Laurie Gay, Julia A Elvin, David L Rimm, Yuting Liu, Elena Ratner, Peter E Schwartz, Alessandro D Santin
PURPOSE: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed. EXPERIMENTAL DESIGN: We describe a heavily pretreated ovarian cancer patient with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune check-point inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (ie, automated quantitative analysis, AQUA) and whole exome sequencing (WES) techniques...
January 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Beatriz de Diego-Diaz, Laura Treu, Stefano Campanaro, Vinicius da Silva Duarte, Alessio Saviane, Silvia Cappellozza, Andrea Squartini
The whole genome sequence of Enterococcus mundtii strain EM01 is reported here. The isolate proved to be the cause of flacherie in Bombyx mori To date, the genomes of 11 other E. mundtii strains have been sequenced. EM01 is the only strain that displayed active pathological effects on its associated animal species.
January 18, 2018: Genome Announcements
Hidewaki Nakagawa, Masashi Fujita
Explosive advances of next-generation sequencer (NGS) and computational analyses have been exploring somatic protein-altered mutations in most cancer types and these coding mutation data are intensively accumulated. However, there is limited information on somatic mutations in non-coding regions including introns, regulatory elements, and non-coding RNAs, structural variants and pathogen in cancer genomes remain widely unexplored. Whole genome sequencing (WGS) approaches can comprehensively explore all types of genomic alterations in cancer and help us to better understand the whole landscape of driver mutations and mutational signature in cancer genomes and elucidate functional or clinical implications of these unexplored genomic regions and mutational signature...
January 18, 2018: Cancer Science
Amy E McCart Reed, Jamie R Kutasovic, Katia Nones, Jodi M Saunus, Leonard Da Silva, Felicity Newell, Stephen Kazakoff, Lewis Melville, Janani Jayanthan, Ana Cristina Vargas, Lynne E Reid, Jonathan Beesley, Xiao Qing Chen, Anne Marie Patch, D David Clouston, Alan Porter, Elizabeth Evans, John V Pearson, Georgia Chenevix-Trench, Margaret C Cummings, Nic Waddell, Sunil R Lakhani, Peter T Simpson
Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are an archetypal example of intra-tumour morphological heterogeneity. The mechanisms underlying coexistence of these different morphologic entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinico-pathological analysis of a cohort of 82 MDLs and found: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was normal in the ductal component in 77...
January 18, 2018: Journal of Pathology
S B Dreyer, N B Jamieson, R Upstill-Goddard, P J Bailey, C J McKay, A V Biankin, D K Chang
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas...
January 2018: British Journal of Surgery
Kang-Sheng Liu, Tai-Ping Li, Hua Ton, Xiao-Dong Mao, Ya-Jun Chen
OBJECTIVE: Advances in genomics and molecular biology have led to the discovery of a large group of uncharacterized long noncoding RNAs (lncRNAs). Emerging evidence indicated that many lncRNAs function in multiple biological processes and its dysregulation often causes diseases. Recent studies suggested that almost all regulatory lncRNAs interact with biological macromolecules such as DNA, RNA, and protein. LncRNAs regulate gene expression mainly on three levels, including epigenetic modification, transcription, and posttranscription, through DNA methylation, histone modification, and chromatin remodeling...
January 20, 2018: Chinese Medical Journal
Atsushi Yamada, Pingjian Yu, Wei Lin, Yoshinaga Okugawa, C Richard Boland, Ajay Goel
Long non-coding RNAs (lncRNAs) have been implicated in human pathology, however, their role in colorectal carcinogenesis have not been fully elucidated. In the current study, whole-transcriptome analysis was performed in 3 pairs of colorectal cancer (CRC) and matched normal mucosa (NM) by RNA sequencing (RNA-seq). Followed by confirmation using the Cancer Genome Atlas (TCGA) dataset, we identified 27 up-regulated and 22 down-regulated lncRNAs in CRC. Up-regulation of four lncRNAs, hereby named colorectal cancer associated lncRNA (CRCAL)-1 [AC021218...
January 12, 2018: Scientific Reports
Jasmine Jacob-Hirsch, Eran Eyal, Binyamin A Knisbacher, Jonathan Roth, Karen Cesarkas, Chen Dor, Sarit Farage-Barhom, Vered Kunik, Amos J Simon, Moran Gal, Michal Yalon, Sharon Moshitch-Moshkovitz, Rick Tearle, Shlomi Constantini, Erez Y Levanon, Ninette Amariglio, Gideon Rechavi
Neural progenitor cells undergo somatic retrotransposition events, mainly involving L1 elements, which can be potentially deleterious. Here, we analyze the whole genomes of 20 brain samples and 80 non-brain samples, and characterized the retrotransposition landscape of patients affected by a variety of neurodevelopmental disorders including Rett syndrome, tuberous sclerosis, ataxia-telangiectasia and autism. We report that the number of retrotranspositions in brain tissues is higher than that observed in non-brain samples and even higher in pathologic vs normal brains...
January 12, 2018: Cell Research
Joshua G Tweedy, Eric Escriva, Maya Topf, Ursula A Gompels
Tissue-culture adaptation of viruses can modulate infection. Laboratory passage and bacterial artificial chromosome (BAC)mid cloning of human cytomegalovirus, HCMV, resulted in genomic deletions and rearrangements altering genes encoding the virus entry complex, which affected cellular tropism, virulence, and vaccine development. Here, we analyse these effects on the reference genome for related betaherpesviruses, Roseolovirus, human herpesvirus 6A (HHV-6A) strain U1102. This virus is also naturally "cloned" by germline subtelomeric chromosomal-integration in approximately 1% of human populations, and accurate references are key to understanding pathological relationships between exogenous and endogenous virus...
December 31, 2017: Viruses
Jun-Yi Zhu, Yulong Fu, Adam Richman, Zhe Han
Genomic sequencing efforts can implicate large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system to validate candidate gene association with pathology is therefore useful. We present such a system employing Drosophila to validate candidate congenital heart disease (CHD) genes. The protocols exploit comprehensive libraries of UAS-GeneX-RNAi fly strains that when crossed into a 4×Hand-Gal4 genetic background afford highly efficient cardiac-specific knockdown of endogenous fly orthologs of human genes...
June 20, 2017: Bio-protocol
Aubrey L Miller, Patrick L Garcia, Joseph G Pressey, Elizabeth A Beierle, David R Kelly, David K Crossman, Leona N Council, Richard Daniel, Raymond G Watts, Stuart L Cramer, Karina J Yoon
Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors...
December 19, 2017: Scientific Reports
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