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https://www.readbyqxmd.com/read/28726809/genomic-diagnostics-within-a-medically-underserved-population-efficacy-and-implications
#1
Kevin A Strauss, Claudia Gonzaga-Jauregui, Karlla W Brigatti, Katie B Williams, Alejandra K King, Cristopher Van Hout, Donna L Robinson, Millie Young, Kavita Praveen, Adam D Heaps, Mindy Kuebler, Aris Baras, Jeffrey G Reid, John D Overton, Frederick E Dewey, Robert N Jinks, Ian Finnegan, Scott J Mellis, Alan R Shuldiner, Erik G Puffenberger
PurposeWe integrated whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) into a clinical workflow to serve an endogamous, uninsured, agrarian community.MethodsSeventy-nine probands (newborn to 49.8 years) who presented between 1998 and 2015 remained undiagnosed after biochemical and molecular investigations. We generated WES data for probands and family members and vetted variants through rephenotyping, segregation analyses, and population studies.ResultsThe most common presentation was neurological disease (64%)...
July 20, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28726122/beta-ketothiolase-deficiency-presenting-with-metabolic-stroke-after-a-normal-newborn-screen-in-two-individuals
#2
Monica H Wojcik, Klaas J Wierenga, Lance H Rodan, Inderneel Sahai, Sacha Ferdinandusse, Casie A Genetti, Meghan C Towne, Roy W A Peake, Philip M James, Alan H Beggs, Catherine A Brownstein, Gerard T Berry, Pankaj B Agrawal
Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase) deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization that predisposes to episodic ketoacidosis. It results from biallelic pathogenic variants in the ACAT1 gene, encoding mitochondrial beta-ketothiolase. We report two cases of beta-ketothiolase deficiency presenting with acute ketoacidosis and "metabolic stroke." The first patient presented at 28 months of age with metabolic acidosis and pallidal stroke in the setting of a febrile gastrointestinal illness...
July 20, 2017: JIMD Reports
https://www.readbyqxmd.com/read/28725025/an-atypical-case-of-spg56-cyp2u1-related-spastic-paraplegia-presenting-with-delayed-myelination
#3
Gaku Minase, Satoko Miyatake, Shin Nabatame, Hiroshi Arai, Eriko Koshimizu, Takeshi Mizuguchi, Mitsuko Nakashima, Noriko Miyake, Hirotomo Saitsu, Toshinobu Miyamoto, Kazuo Sengoku, Naomichi Matsumoto
Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms. Biallelic mutations in the cytochrome P450 2U1 gene (CYP2U1) are associated with spastic paraplegia type 56 (SPG56), manifesting both uncomplicated and complicated HSP. Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging...
July 20, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28724397/partial-uniparental-isodisomy-of-chromosome-16-unmasks-a-deleterious-biallelic-mutation-in-ift140-that-causes-mainzer-saldino-syndrome
#4
Benjamin M Helm, Jason R Willer, Azita Sadeghpour, Christelle Golzio, Eric Crouch, Samantha Schrier Vergano, Nicholas Katsanis, Erica E Davis
BACKGROUND: The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings...
July 19, 2017: Human Genomics
https://www.readbyqxmd.com/read/28722338/hdr-del-a-tool-based-on-hamming-distance-for-prioritizing-pathogenic-chromosomal-deletions-in-exome-sequencing
#5
Atsuko Imai, Masakazu Kohda, Kaori Kobayashi, Tomoko Hirata, Yasushi Sakata, Kei Murayama, Akira Ohtake, Yasushi Okazaki, Akihiro Nakaya, Jurg Ott
High-density oligonucleotide arrays have been widely used to detect pathogenic chromosomal deletions. In addition to high-density oligonucleotide arrays, programs using whole exome sequencing have become available for estimating copy number variations using depth of coverage. Here we propose a new statistical method, HDR-del, to prioritize pathogenic chromosomal deletions based on Hamming distance in exome sequencing. In vcf (Variant Call Format) files generated from exome sequencing, hemizygous chromosomal deletion regions lack heterozygous variants and lead to apparent long runs of homozygosity (ROH)...
July 19, 2017: Human Mutation
https://www.readbyqxmd.com/read/28722276/identification-and-functional-analysis-of-an-adamtsl1-variant-associated-with-a-complex-phenotype-including-congenital-glaucoma-craniofacial-and-other-systemic-features-in-a-three-generation-human-pedigree
#6
Kathryn Hendee, Lauren Weiping Wang, Linda M Reis, Gregory M Rice, Suneel S Apte, Elena V Semina
Developmental glaucoma can occur as an isolated or syndromic condition and is genetically heterogeneous. We describe a three-generation family affected with developmental glaucoma, myopia, and/or retinal defects associated with variable craniofacial/dental, auditory, brain, renal, and limb anomalies. Whole exome sequencing identified a heterozygous c.124T> C, p.(Trp42Arg) allele in ADAMTSL1; co-segregation analysis confirmed the presence of this allele in four affected family members. The mutation affects a highly conserved residue and is strongly predicted to have a deleterious effect on protein function...
July 19, 2017: Human Mutation
https://www.readbyqxmd.com/read/28722124/pancreatic-undifferentiated-carcinoma-with-osteoclast-like-giant-cells-is-genetically-similar-to-but-clinically-distinct-from-conventional-ductal-adenocarcinoma
#7
Claudio Luchini, Antonio Pea, Gemma Lionheart, Andrea Mafficini, Alessia Nottegar, Nicola Veronese, Peter Chianchiano, Lodewijk A A Brosens, Michaël Noë, G Johan A Offerhaus, Raluca Yonescu, Yi Ning, Giuseppe Malleo, Giulio Riva, Paola Piccoli, Ivana Cataldo, Paola Capelli, Giuseppe Zamboni, Aldo Scarpa, Laura D Wood
Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGC, including the whole exome sequencing of 8 UCOGC. We observed that 60% of the UCOGC contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm...
July 19, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28721938/practical-clues-for-diagnosing-wwox-encephalopathy
#8
Oana Tarta-Arsene, Diana Barca, Dana Craiu, Catrinel Iliescu
The WW domain-containing oxidoreductase gene is implicated in autosomal recessive disorders of the central nervous system, expressed either as spinocerebellar ataxia or as a severe form with early-infantile epileptic encephalopathy. Here, we describe the electroclinical evolution of these disorders, adding new diagnostic clues based on a case study. The patient, a boy with early-onset epilepsy, presented with profound global developmental delay, persistent hypsarrhythmia, and epileptic spasms, associated with progressive cerebral atrophy without microcephaly...
July 19, 2017: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/28721681/genetic-characterization-and-disease-mechanism-of-retinitis-pigmentosa-current-scenario
#9
REVIEW
Muhammad Umar Ali, Muhammad Saif Ur Rahman, Jiang Cao, Ping Xi Yuan
Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X-linked, autosomal dominant or autosomal recessive manner...
August 2017: 3 Biotech
https://www.readbyqxmd.com/read/28720891/whole-exome-sequencing-reveals-inherited-and-de-novo-variants-in-autism-spectrum-disorder-a-trio-study-from-saudi-families
#10
Bashayer Al-Mubarak, Mohamed Abouelhoda, Aisha Omar, Hesham AlDhalaan, Mohammed Aldosari, Michael Nester, Hussain A Alshamrani, Mohamed El-Kalioby, Ewa Goljan, Renad Albar, Shazia Subhani, Asma Tahir, Sultana Asfahani, Alaa Eskandrani, Ahmed Almusaiab, Amna Magrashi, Jameela Shinwari, Dorota Monies, Nada Al Tassan
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity. The interplay of de novo and inherited rare variants has been suspected in the development of ASD. Here, we applied whole exome sequencing (WES) on 19 trios from singleton Saudi families with ASD. We developed an analysis pipeline that allows capturing both de novo and inherited rare variants predicted to be deleterious. A total of 47 unique rare variants were detected in 17 trios including 38 which are newly discovered...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720843/clinical-study-of-genomic-drivers-in-pancreatic-ductal-adenocarcinoma
#11
Michael T Barrett, Ray Deiotte, Elizabeth Lenkiewicz, Smriti Malasi, Tara Holley, Lisa Evers, Richard G Posner, Timothy Jones, Haiyong Han, Mark Sausen, Victor E Velculescu, Jeffrey Drebin, Peter O'Dwyer, Gayle Jameson, Ramesh K Ramanathan, Daniel D Von Hoff
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples...
July 18, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28720148/multifocal-gastric-adenocarcinoma-in-a-patient-with-lrba-deficiency
#12
Nina Bratanič, Jernej Kovač, Katka Pohar, Katarina Trebušak Podkrajšek, Alojz Ihan, Tadej Battelino, Magdalena Avbelj Stefanija
BACKGROUND: Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We describe a case history of a young adult with LRBA deficiency and two independent malignancies. METHODS: Family-trio whole exome sequencing with unbiased phenotype ontology approach was used for identification of causative mutations of a primary immune deficiency disorder...
July 18, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28720077/hemolytic-uremic-syndrome-as-the-presenting-manifestation-of-wt1-mutation-and-denys-drash-syndrome-a-case-report
#13
Joseph L Alge, Scott E Wenderfer, John Hicks, Mir Reza Bekheirnia, Deborah A Schady, Jamey S Kain, Michael C Braun
BACKGROUND: Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in the setting of glomerular diseases, and it has been described in association with Denys-Drash syndrome (DDS), which is characterized by the triad of abnormal genitourinary development; a pathognomonic glomerulopathy, diffuse mesangial sclerosis; and the development of Wilms tumor. CASE PRESENTATION: We report the case of a 46, XX female infant who presented with HUS and biopsy-proven thrombotic microangiopathy...
July 18, 2017: BMC Nephrology
https://www.readbyqxmd.com/read/28719906/a-common-ancestral-asn242ser-mutation-in-tmem67-identified-in-multiple-iranian-families-with-joubert-syndrome
#14
MohammadReza Dehghani, Majid Mojarad, Ehsan Ghayoor Karimiani, Mohammad Yahya Vahidi Mehrjardi, Afsaneh Sahebalzamani, Farah Ashrafzadeh, Mehran Beiraghi Toosi, Atiyeh Eslahi, Najmeh Ahangari, Seyed Mojtaba Yassini, Afsaneh Hassanbeigi, Azam Rasti, Seyed Mehdi Kalantar, Reza Maroofian
BACKGROUND: Joubert syndrome (JS) is a clinically and genetically heterogeneous group of rare neurodevelopmental disorder characterised by peculiar midbrain-hindbrain malformation, known as the "molar tooth" sign. JS can manifest a broad range of signs and symptoms. The most common features of JS are hypotonia, ataxia, developmental delay/intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been shown to cause JS. METHODS: We employed whole-genome single nucleotide polymorphism genotyping in a group of Iranian families with JS and Sanger sequencing of a known mutation associated with JS located in a single homozygous regions shared by affected members of the families...
July 19, 2017: Public Health Genomics
https://www.readbyqxmd.com/read/28719387/pediatric-mitochondrial-diseases-and-the-heart
#15
Gregory M Enns
PURPOSE OF REVIEW: Mitochondrial disorders are an increasingly recognized cause of heart dysfunction, with the primary manifestations being cardiomyopathy and conduction defects. This review focuses on the complex genetics of mitochondrial disease and recently discovered conditions that affect mitochondrial function. RECENT FINDINGS: Next-generation sequencing techniques, especially whole-exome sequencing, have led to the discovery of a number of conditions that cause mitochondrial dysfunction and subsequent cardiac abnormalities...
July 17, 2017: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/28717666/whole-exome-sequencing-and-dna-methylation-analysis-in-a-clinical-amyotrophic-lateral-sclerosis-cohort
#16
Fleur C Garton, Beben Benyamin, Qiongyi Zhao, Zhijun Liu, Jacob Gratten, Anjali K Henders, Zong-Hong Zhang, Janette Edson, Sarah Furlong, Sarah Morgan, Susan Heggie, Kathryn Thorpe, Casey Pfluger, Karen A Mather, Perminder S Sachdev, Allan F McRae, Matthew R Robinson, Sonia Shah, Peter M Visscher, Marie Mangelsdorf, Robert D Henderson, Naomi R Wray, Pamela A McCombe
BACKGROUND: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. METHODS: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations...
July 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28716744/a-heterozygous-mutation-in-got1-is-associated-with-familial-macro-aspartate-aminotransferase
#17
Maria Kulecka, Aldona Wierzbicka, Agnieszka Paziewska, Michal Mikula, Andrzej Habior, Wojciech Janczyk, Michalina Dabrowska, Jakub Karczmarski, Michal Lazniewski, Krzysztof Ginalski, Anna Czlonkowska, Piotr Socha, Jerzy Ostrowski
BACKGROUND & AIMS: Macro-aspartate aminotransferase (macro-AST) manifests as persistent elevation of AST levels, due to association of the protein with immunoglobulins in the circulation macro-AST is a rare, benign condition without a previously confirmed genetic basis. METHODS: Whole exome sequencing (WES)-based screening was performed on 32 participants with suspected familial macro-AST, while variants validation was performed on an extended cohort of 90 probands and 1644 healthy controls using Taqman genotyping...
July 14, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28716623/a-second-truncation-in-ttn-causes-early-onset-recessive-muscular-dystrophy
#18
Elizabeth Harris, Ana Töpf, Anna Vihola, Anni Evilä, Rita Barresi, Judith Hudson, Peter Hackman, Brian Herron, Daniel MacArthur, Hanns Lochmüller, Kate Bushby, Bjarne Udd, Volker Straub
Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies ±cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD...
June 22, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28716262/new-genetic-causes-for-complex-hereditary-spastic-paraplegia
#19
Paulo Victor Sgobbi de Souza, Thiago Bortholin, Renan Braido Dias, Marco Antônio Troccoli Chieia, Stênio Burlin, Fernando George Monteiro Naylor, Wladimir Bocca Vieira de Rezende Pinto, Acary Souza Bulle Oliveira
INTRODUCTION: Hereditary Spastic Paraplegia (HSP) represents a complex and heterogeneous group of rare neurodegenerative disorders that share a common clinical feature of weakness and lower limb spasticity that can occur alone or in combination with a constellation of other neurological or systemic signs and symptoms. Although the core clinical feature of weakness and lower limb spasticity is virtually universal, the genetic heterogeneity is almost uncountable with more than 70 genetic forms described so far...
August 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28716121/identification-of-trunk-mutations-in-gastric-carcinoma-a-case-study
#20
Zhan Zhou, Shanshan Wu, Jun Lai, Yuan Shi, Chixiao Qiu, Zhe Chen, Yufeng Wang, Xun Gu, Jie Zhou, Shuqing Chen
BACKGROUND: Intratumor heterogeneity (ITH) poses an urgent challenge for cancer precision medicine because it can cause drug resistance against cancer target therapy and immunotherapy. The search for trunk mutations that are present in all cancer cells is therefore critical for each patient. CASE PRESENTATION: In this study, we aimed to evaluate the efficiency of multiregional sequencing for the identification of trunk mutations present in all regions of a tumor as a case study...
July 17, 2017: BMC Medical Genomics
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