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Ed M Dicks, Jonthan P Tyrer, Suzana Ezquina, Michelle Jones, John Baierl, Pei-Chen Peng, Michael Diaz, Ellen Goode, Stacey J Winham, Thilo Dörk, Toon Van Gorp, Ana De Fazio, David Bowtell, Kunle Odunsi, Kirsten Moysich, Marina Pavanello, Ian Campbell, James D Brenton, Susan J Ramus, Simon A Gayther, Paul D P Pharoah
Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls...
April 3, 2024: medRxiv
#2
REVIEW
Jennifer R Brown
Our understanding of risk factors for the development of chronic lymphocytic leukemia (CLL) is still incomplete and includes genetic and environmental factors. CLL is one of the most familial of all cancers, yet common high-penetrance risk alleles have not been identified. Genome-wide association studies have identified many common variants with low relative risks, whereas exome-wide rare variant analysis has implicated ATM in CLL causation. Environmental factors have also been challenging to identify given the limited understanding of the relevant time period of exposure relative to diagnosis, and the inability to quantify past exposures...
April 2024: Journal of the National Comprehensive Cancer Network: JNCCN
#3
JOURNAL ARTICLE
Jessica Petiti, Ymera Pignochino, Aurora Schiavon, Emilia Giugliano, Enrico Berrino, Giorgia Giordano, Federico Itri, Matteo Dragani, Daniela Cilloni, Marco Lo Iacono
Acute myeloid leukemia (AML) is a complex hematologic malignancy with high morbidity and mortality. Nucleophosmin 1 (NPM1) mutations occur in approximately 30% of AML cases, and NPM1-mutated AML is classified as a distinct entity. NPM1-mutated AML patients without additional genetic abnormalities have a favorable prognosis. Despite this, 30-50% of them experience relapse. This study aimed to investigate the potential of total RNAseq in improving the characterization of NPM1-mutated AML patients. We explored genetic variations independently of myeloid stratification, revealing a complex molecular scenario...
March 24, 2024: International Journal of Molecular Sciences
#4
JOURNAL ARTICLE
Christian Lundtoft, Ann Knight, Jennifer R S Meadows, Åsa Karlsson, Solbritt Rantapää-Dahlqvist, Ewa Berglin, Øyvind Palm, Hilde Haukeland, Iva Gunnarsson, Annette Bruchfeld, Mårten Segelmark, Sophie Ohlsson, Aladdin J Mohammad, Per Eriksson, Peter Söderkvist, Lars Ronnblom, Roald Omdal, Roland Jonsson, Kerstin Lindblad-Toh, Johanna Dahlqvist
OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited...
April 4, 2024: RMD Open
#5
JOURNAL ARTICLE
Gabrielle Lemire, Alba Sanchis-Juan, Kathryn Russell, Samantha Baxter, Katherine R Chao, Moriel Singer-Berk, Emily Groopman, Isaac Wong, Eleina England, Julia Goodrich, Lynn Pais, Christina Austin-Tse, Stephanie DiTroia, Emily O'Heir, Vijay S Ganesh, Monica H Wojcik, Emily Evangelista, Hana Snow, Ikeoluwa Osei-Owusu, Jack Fu, Mugdha Singh, Yulia Mostovoy, Steve Huang, Kiran Garimella, Samantha L Kirkham, Jennifer E Neil, Diane D Shao, Christopher A Walsh, Emanuela Argilli, Carolyn Le, Elliott H Sherr, Joseph G Gleeson, Shirlee Shril, Ronen Schneider, Friedhelm Hildebrandt, Vijay G Sankaran, Jill A Madden, Casie A Genetti, Alan H Beggs, Pankaj B Agrawal, Kinga M Bujakowska, Emily Place, Eric A Pierce, Sandra Donkervoort, Carsten G Bönnemann, Lyndon Gallacher, Zornitza Stark, Tiong Yang Tan, Susan M White, Ana Töpf, Volker Straub, Mark D Fleming, Martin R Pollak, Katrin Õunap, Sander Pajusalu, Kirsten A Donald, Zandre Bruwer, Gianina Ravenscroft, Nigel G Laing, Daniel G MacArthur, Heidi L Rehm, Michael E Talkowski, Harrison Brand, Anne O'Donnell-Luria
Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform...
March 27, 2024: American Journal of Human Genetics
#6
Aisha T Alfaraidi, Nahed K ALSulimani, Wallaa Garout
MEGDEL syndrome, a rare autosomal recessive disorder characterized by 3-methylglutaconic aciduria, deafness, encephalopathy, and Leigh-like syndrome, results from mutations in the SERAC1 gene. This case report explores the clinical presentation, diagnostic challenges, and genetic findings of an 11-year-old boy with MEGDEL syndrome at a tertiary care center in Saudi Arabia. The patient, born to consanguineous parents, presented with developmental delay, cerebral palsy, intellectual disability, and seizures. Diagnostic evaluation at 15 months revealed 3-methylglutaconic aciduria, and subsequent genetic testing through whole exome sequencing confirmed a rare homozygous deletion variant in the SERAC1 gene...
March 2024: Curēus
#7
JOURNAL ARTICLE
Esra Isik, Yesim Aydinok, Canan Albayrak, Basak Durmus, Zeynep Karakas, Mehmet Fatih Orhan, Nazan Sarper, Sultan Aydın, Selma Unal, Yesim Oymak, Nihal Karadas, Aysen Turedi, Davut Albayrak, Funda Tayfun, Deniz Tugcu, Serap Karaman, Mahmut Tobu, Ekrem Unal, Alper Ozcan, Sule Unal, Tekin Aksu, Aysegul Unuvar, Mustafa Bilici, Fatih Azik, Yilmaz Ay, Sema Aylan Gelen, Emine Zengin, Esin Albudak, Ibrahim Eker, Taner Karakaya, Ozgur Cogulu, Ferda Ozkinay, Tahir Atik
OBJECTIVES: In congenital hemolytic anemias (CHA), it is not always possible to determine the specific diagnosis by evaluating clinical findings and conventional laboratory tests. The aim of this study is to evaluate the utility of next-generation sequencing (NGS) and clinical-exome-based copy number variant (CNV) analysis in patients with CHA. METHODS: One hundred and forty-three CHA cases from 115 unrelated families referred for molecular analysis were enrolled in the study...
March 31, 2024: European Journal of Haematology
#8
JOURNAL ARTICLE
Maureen Jacob, Melanie Brugger, Stephanie Andres, Matias Wagner, Elisabeth Graf, Riccardo Berutti, Erik Tilch, Martin Pavlov, Katharina Mayerhanser, Julia Hoefele, Thomas Meitinger, Juliane Winkelmann, Theresa Brunet
In patients with neurodevelopmental disorders (NDDs), exome sequencing (ES), the diagnostic gold standard, reveals an underlying monogenic condition in only approximately 40% of cases. We report the case of a female patient with profound NDD who died 30 years ago at the age of 3 years and for whom genome sequencing (GS) now identified a single-exon deletion in TBCK previously missed by ExomeDepth, the copy number variation (CNV) detection algorithm in ES.Deoxyribonucleic acid (DNA) was extracted from frozen muscle tissue of the index patient and the parents' blood...
March 28, 2024: Neuropediatrics
#9
JOURNAL ARTICLE
Chandrashekar Karunakaran, Vidya Niranjan, Anagha S Setlur, Dhanya Pradeep, Jitendra Kumar
INTRODUCTION: Colorectal cancers are the world's third most commonly diagnosed type of cancer. Currently, there are several diagnostic and treatment options to combat it. However, a delay in detection of the disease is life-threatening. Additionally, a thorough analysis of the exomes of cancers reveals potential variation data that can be used for early disease prognosis. METHODS: By utilizing a comprehensive computational investigation, the present study aimed to reveal mutations that could potentially predispose to colorectal cancer...
February 23, 2024: Current Genomics
#10
JOURNAL ARTICLE
Jing Wei, Boyang Jason Wu, Sayed S Daoud
Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients...
March 13, 2024: Genes
#11
JOURNAL ARTICLE
Kemeng Liu, Jiewen Fu, Kan Guo, Mazaher Maghsoudloo, Jingliang Cheng, Junjiang Fu
Hereditary hemorrhagic telangiectasia (HHT), also called Rendu-Osler syndrome, is a group of rare genetic diseases characterized by autosomal dominance, multisystemic vascular dysplasia, and age-related penetrance. This includes arteriovenous malformations (AVMs) in the skin, brain, lung, liver, and mucous membranes. The correlations between the phenotype and genotype for HHT are not clear. An HHT Chinese pedigree was recruited. Whole exome sequencing (WES) analysis, Sanger verification, and co-segregation were conducted...
February 27, 2024: Genes
#12
Mariana Correia Marques, Danielle Rubin, Emily Shuldiner, Mallika Datta, Elizabeth Schmitz, Gustavo Gutierrez Cruz, Andrew Patt, Elizabeth Bennett, Alexei Grom, Dirk Foell, Marco Gattorno, John Bohnsack, Rae S M Yeung, Sampath Prahalad, Elizabeth Mellins, Jordi Anton, Claudio Arnaldo Len, Sheila Oliveira, Patricia Woo, Seza Ozen, Zuoming Deng, Michael J Ombrello
OBJECTIVE: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). METHODS: Targeted sequencing of HLH genes ( LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D ) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package...
March 15, 2024: medRxiv
#13
JOURNAL ARTICLE
S Zucca, G Nicora, F De Paoli, M G Carta, R Bellazzi, P Magni, E Rizzo, I Limongelli
Identifying disease-causing variants in Rare Disease patients' genome is a challenging problem. To accomplish this task, we describe a machine learning framework, that we called "Suggested Diagnosis", whose aim is to prioritize genetic variants in an exome/genome based on the probability of being disease-causing. To do so, our method leverages standard guidelines for germline variant interpretation as defined by the American College of Human Genomics (ACMG) and the Association for Molecular Pathology (AMP), inheritance information, phenotypic similarity, and variant quality...
March 23, 2024: Human Genetics
#14
JOURNAL ARTICLE
Yunus Emre Cebeci, Rumeysa Aslihan Erturk, Mehmet Arif Ergun, Mehmet Baysan
BACKGROUND: Next-generation sequencing (NGS) technologies offer fast and inexpensive identification of DNA sequences. Somatic sequencing is among the primary applications of NGS, where acquired (non-inherited) variants are based on comparing diseased and healthy tissues from the same individual. Somatic mutations in genetic diseases such as cancer are tightly associated with genomic instability. Genomic instability increases heterogenity, complicating sequencing efforts further, a task already challenged by the presence of short reads and repetitions in human DNA...
March 22, 2024: BMC Bioinformatics
#15
JOURNAL ARTICLE
Danyi Wang, Jayaprakasam Bolleddula, Anna Coenen-Stass, Thomas Grombacher, Jennifer Q Dong, Juergen Scheuenpflug, Giuseppe Locatelli, Zheng Feng
Whole-exome sequencing (WES) is widely used in clinical settings; however, the exploration of its use in pharmacogenomic analysis remains limited. Our study compared the variant callings for 28 core absorption, distribution, metabolism and elimination genes by WES and array-based technology using clinical trials samples. The results revealed that WES had a positive predictive value of 0.71-0.92 and a sensitivity of single-nucleotide variants between 0.68 and 0.95, compared with array-based technology, for the variants in the commonly targeted regions of the WES and PhamacoScan™ assay...
March 21, 2024: Pharmacogenomics
#16
JOURNAL ARTICLE
Mateja Pfeifer, Helga Rehder, Maria Gerykova Bujalkova, Christine Bartsch, Barbara Fritz, Cordula Knopp, Björn Beckers, Frank Dohle, Matthias Meyer-Wittkopf, Roland Axt-Fliedner, Alexander V Beribisky, Manuel Hofer, Franco Laccone, Katharina Schoner
BACKGROUND: In this study we aimed to describe the morphological and pathogenetic differences between tracheal agenesis and tracheal atresia, which are not clearly distinguished from each other in the literature, and to contribute thereby to the understanding and management of these conditions. Both tracheal agenesis and tracheal atresia represent rare disorders of still unknown aetiology that cannot be detected by prenatal ultrasound. If the affected foetuses survive until birth these conditions result in respiratory failure and in futile attempts to rescue the infant's life...
March 12, 2024: Orphanet Journal of Rare Diseases
#17
Justine Serre, Alice Doreille, Laure Raymond, Gaspard Suc, Mickaël Bobot, Marine Dancer, Cédric Rafat, Laurent Mesnard
INTRODUCTION: Hypertensive nephrosclerosis (HN) ranks as one of the most frequent causes of chronic kidney disease (CKD), but its very existence has repeatedly been called into question, especially in young adults. Its diagnostic framework is established chiefly on non-specific clinical criteria and its defining histopathological set of features are in fact shared by numerous other conditions. Genetic testing based on exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in timely fashion in nephrology with a significant number of re-established diagnoses...
March 12, 2024: American Journal of Nephrology
#18
JOURNAL ARTICLE
Ulrik Kristoffer Stoltze, Jon Foss-Skiftesvik, Thomas van Overeem Hansen, Simon Rasmussen, Konrad J Karczewski, Karin A W Wadt, Kjeld Schmiegelow
Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected...
February 29, 2024: Nature Communications
#19
Somayeh Khoddam, Neda Kamal, Amirmasoud Shiri, Hossein Jafari Khamirani, Jamal Manoochehri, Mehdi Dianatpour, Seyed Mohammad Bagher Tabei, Seyed Alireza Dastgheib
The PEX11β gene contains four exons and encodes peroxisomal membrane protein 11β, which is involved in peroxisome proliferation and division. Pathogenic variants in this gene result in a rare genetic disorder with autosomal recessive inheritance called peroxisome biogenesis disorder 14B (MIM: 614920). Here, we report two affected siblings with a novel variant (NM_003846: c.11G > A, p. Trp4Ter) in the PEX11β gene that was identified by whole exome sequencing and confirmed by Sanger sequencing...
February 27, 2024: European Journal of Medical Genetics
#20
JOURNAL ARTICLE
Masoumeh Heidari Feizabadi, Masoome Alerasool, Atieh Eslahi, Emran Esmaeilzadeh, Mohammad Yahya Vahidi Mehrjardi, Mitra Saket, Shima Farokhi, Zohreh Fattahi, Hamid Reza Khorram Khorshid, Majid Mojarrad
Bardet-Biedl syndrome (BBS) is a rare inherited ciliopathy disorder characterized by a broad spectrum of clinical symptoms such as retinal dystrophy, obesity, polydactyly, genitourinary and kidney anomalies, learning disability, and hypogonadism. The understanding of the variants involved in BBS-causing genes remains incomplete, highlighting the need for further research to develop a molecular diagnostic strategy for this syndrome. Singleton whole-exome sequencing (WES) was performed on sixteen patients. Our study revealed (1) nine patients carried eight homozygous pathogenic variants with four of them being novel (2) Specifically, a synonymous splicing variant (c...
February 26, 2024: Biochemical Genetics
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