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Genetic mutations

Christoph Niemietz, Christoph Röcken, Matthias Schilling, Jörg Stypman, Constantin E Uhlig, Hartmut H-J Schmidt
Transthyretin-related Familial Amyloid Polyneuropathy (ATTR Amyloidosis, former FAP, here called TTR-FAP) is a rare, progressive autosomal dominant inherited amyloid disease ending fatal within 5 - 15 years after final diagnosis. TTR-FAP is caused by mutations of transthyretin (TTR), which forms amyloid fibrils affecting peripheral and autonomic nerves, the heart and other organs. Due to the phenotypic heterogeneity and partly not specific enough clinical symptoms, diagnosis of TTR-FAP can be complicated...
March 2018: Deutsche Medizinische Wochenschrift
Dian He, Yuan Li, Yunli Yu, Gang Cai, Fu Ouyang, Yuchan Lin, Hongjuan Lu, Lan Chu
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder that primarily affects the skin and the nervous system. This condition is called segmental NF1 (also called neurofibromatosis type V) when clinical features are limited to one area of the body. Segmental NF1 is generally thought to result from somatic mosaicism due to a postzygotic mutation in the NF1 gene, thus a test for NF1 gene abnormalities in peripheral blood is usually negative. Here we report a 31-year-old male presenting with epileptic seizures, who had a history of neurofibromas confirmed by biopsy, but lacked a family history of neurofibromatosis...
March 1, 2018: Clinical Neurology and Neurosurgery
Diana Olvera, Rachel Stolzenfeld, Joan C Marini, Michelle S Caird, Kenneth M Kozloff
Osteogenesis imperfecta (OI) is a genetic disorder characterized by altered bone quality and imbalanced bone remodeling, leading to skeletal fractures which are most prominent during childhood. Treatments for OI have focused on restoring pediatric bone density and architecture to recover functional strength and consequently reduce fragility. Though antiresorptive agents like bisphosphonates (BP) are currently the most common intervention for the treatment of OI, a number of studies have shown efficacy of sclerostin antibody (SclAb) in inducing gains in bone mass and reducing fragility in OI mouse models...
March 15, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Aleksandra Augusciak-Duma, Joanna Witecka, Aleksander L Sieron, Magdalena Janeczko, Jacek J Pietrzyk, Karolina Ochman, Anna Galicka, Maria K Borszewska-Kornacka, Jacek Pilch, Elzbieta Jakubowska-Pietkiewicz
Although over 85% of osteogenesis imperfecta (OI) cases are associated with mutations in the procollagen type I genes (COL1A1 or COL1A2), no hot spots for the mutations were associated with particular clinical phenotypes. Eight patients that were studied here, diagnosed with OI by clinical standards, are from the Polish population with no ethnic background indicated. Previously unpublished mutations were found in six out of those eight patients. Genotypes for polymorphisms (Sp1 - rs1800012 and PvuII - rs412777), linked to bone formation and metabolism were determined...
March 15, 2018: Acta Biochimica Polonica
ChengLin Zhong, SiChen Li, JingJing Li, FengPeng Li, MingXia Ran, LingYun Qiu, DiYan Li, Qing Zhu, Yan Wang, HuaDong Yin, Gang Shu, Chaowu Yang, XiaoLing Zhao
Peroxisome proliferator activated receptor-alpha (PPARα) and Egl nine homolog 3 (EGLN3) play critical roles in facilitating the adaptation to a hypoxic environment. However, the relationship between EGLN3 and PPARα variants and hypoxic adaptation remains poorly understood in Tibetan chickens. To better understand the effects of genetic variation, we sequenced exons of PPARα and EGLN3 in 138 Lowland chickens (LC) from 7 breeds that were located in Emei, Miyi, Shimian, Wanyuan, Pengxian, and Muchuan in the Sichuan province, and Wenchang in the Hainan province (altitudes for these locations are below 1800 meters)...
2018: PloS One
Vincent Plagnol, Samuel Woodhouse, Karen Howarth, Stefanie Lensing, Matt Smith, Michael Epstein, Mikidache Madi, Sarah Smalley, Catherine Leroy, Jonathan Hinton, Frank de Kievit, Esther Musgrave-Brown, Colin Herd, Katherine Baker-Neblett, Will Brennan, Peter Dimitrov, Nathan Campbell, Clive Morris, Nitzan Rosenfeld, James Clark, Davina Gale, Jamie Platt, John Calaway, Greg Jones, Tim Forshew
Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA...
2018: PloS One
Mary M Alleman, Rohit Chitale, Cara C Burns, Jane Iber, Naomi Dybdahl-Sissoko, Qi Chen, Djo-Roy Van Koko, Raimi Ewetola, Yogolelo Riziki, Hugo Kavunga-Membo, Cheikh Dah, Rija Andriamihantanirina
The last confirmed wild poliovirus (WPV) case in Democratic Republic of the Congo (DRC) had paralysis onset in December 2011 (1). DRC has had cases of vaccine-derived polioviruses (VDPVs) documented since 2004 (Table 1) (1-6). After an outbreak of 30 circulating VDPV type 2 (cVDPV2) cases during 2011-2012, only five VDPV2 cases were reported during 2013-2016 (Table 1) (1-6). VDPVs can emerge from oral poliovirus vaccine (OPV types 1, 2, or 3; Sabin) polioviruses that have genetically mutated resulting in reversion to neurovirulence...
March 16, 2018: MMWR. Morbidity and Mortality Weekly Report
Blanca De Unamuno, Zaida García-Casado, José Bañuls, Celia Requena, José Antonio Lopez-Guerrero, Eduardo Nagore
CDKN2A germline mutations increase the risk of melanoma development and are present in 20 and 10% of familial and multiple melanoma cases, respectively. Pancreatic cancer has been associated with CDKN2A in some populations and, accordingly, its presence in first-degree or second-degree relatives of a melanoma patient is considered as a criterion for genetic testing. In this study, we show that in an area with low melanoma incidence, CDKN2A germline mutations in patients with melanoma and personal or family history of pancreatic cancer are mainly present in the setting of familial or multiple melanoma cases...
March 14, 2018: Melanoma Research
Jennifer Karmouch, Alexandros Protonotarios, Petros Syrris
PURPOSE OF REVIEW: To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM...
March 14, 2018: Current Opinion in Cardiology
Jacob W P Potuijt, Martijn Baas, Rivka Sukenik-Halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renée Gallagher, Sigrid M Swagemakers, Steven E R Hovius, Christianne A van Nieuwenhoven, Robert-Jan H Galjaard, Peter J van der Spek, Nadav Ahituv, Annelies de Klein
PurposeThe zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud...
March 15, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Rachel C Lombardo, Aleksey Porollo, James F Cnota, Robert J Hopkin
PurposeCongenital central hypoventilation syndrome (CCHS, OMIM 209880) is a rare autosomal dominant disorder caused by mutation in PHOX2B that manifests as a consequence of abnormal neural crest cell migration during embryogenesis. Unlike other neurocristopathies, however, its impact on the cardiovascular system has not been previously assessed. This study was an effort to characterize the association between congenital heart disease (CHD) and mutations in PHOX2B in patients with CCHS.MethodsA retrospective review of patients with CCHS in conjunction with functional analysis of PHOX2B mutations associated with CHD was performed...
March 15, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Hiroki Maruyama, Kaori Miyata, Mariko Mikame, Atsumi Taguchi, Chu Guili, Masaru Shimura, Kei Murayama, Takeshi Inoue, Saori Yamamoto, Koichiro Sugimura, Koichi Tamita, Toshihiro Kawasaki, Jun Kajihara, Akifumi Onishi, Hitoshi Sugiyama, Teiko Sakai, Ichijiro Murata, Takamasa Oda, Shigeru Toyoda, Kenichiro Hanawa, Takeo Fujimura, Shigehisa Ura, Mimiko Matsumura, Hideki Takano, Satoshi Yamashita, Gaku Matsukura, Ryushi Tazawa, Tsuyoshi Shiga, Mio Ebato, Hiroshi Satoh, Satoshi Ishii
PurposePlasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females.MethodsBetween 1 July 2014 and 31 December 2015, we screened 2,360 patients (1,324 males) referred from 169 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively...
March 15, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Gernot Kriegshäuser, Dietmar Enko, Hasmik Hayrapetyan, Stepan Atoyan, Christian Oberkanins, Tamara Sarkisian
PurposeThis work aimed at investigating demographic, clinical, and genetic characteristics of individuals experiencing their first familial Mediterranean fever (FMF) attack at age ≥40 years in a very large cohort of Armenian FMF patients.MethodsIn total, 10,370 Armenian patients diagnosed with FMF based on the Tel Hashomer criteria and carrying at least one MEFV mutant allele were included in this study.ResultsA total of 354 (3.40%) patients had late-onset FMF. Of these, 194 (54.80%) were female and 160 (45...
March 15, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Brigitte Royer-Pokora, Manfred Beier, Artur Brandt, Constanze Duhme, Maike Busch, Carmen de Torres, Hans-Dieter Royer, Jaume Mora
Wilms tumors (WT) with WT1 mutations do not respond well to preoperative chemotherapy by volume reduction, suggesting resistance to chemotherapy. The histologic pattern of this tumor subtype indicates an intrinsic mesenchymal differentiation potential. Currently, it is unknown whether cytotoxic treatments can induce a terminal differentiation state as a direct comparison of untreated and chemotherapy-treated tumor samples has not been reported so far. We conducted gene expression profiling of 11 chemotherapy and seven untreated WT1-mutant Wilms tumors and analyzed up- and down-regulated genes with bioinformatic methods...
March 15, 2018: Cancer Medicine
Shivani Mishra, Himani Pandey, Priyanka Srivastava, Kausik Mandal, Shubha R Phadke
OBJECTIVE: To determine the prevalence and spectrum of Connexin 26 (GJB2) mutations in pre-lingual non-syndromic hearing loss (NSHL) patients in authors' centre and to review the data of Indian patients from the literature. METHODS: Sanger sequencing of entire coding region contained in single exon (Exon 2) of GJB2 gene in 15 patients of NSHL. RESULTS: GJB2 mutations were found in 40% (6/15) of NSHL patients, out of which mono-allelic were 33...
March 15, 2018: Indian Journal of Pediatrics
Hiroshi Maeda, Mahin Khatami
For over six decades reductionist approaches to cancer chemotherapies including recent immunotherapy for solid tumors produced outcome failure-rates of 90% (±5) according to governmental agencies and industry. Despite tremendous public and private funding and initial enthusiasm about missile-therapy for site-specific cancers, molecular targeting drugs for specific enzymes such as kinases or inhibitors of growth factor receptors, the outcomes are very bleak and disappointing. Major scientific reasons for repeated failures of such therapeutic approaches are attributed to reductionist approaches to research and infinite numbers of genetic mutations in chaotic molecular environment of solid tumors that are bases of drug development...
March 1, 2018: Clinical and Translational Medicine
Xian Qi, Xiaofei An, Yongjun Jiao, Huiyan Yu, Ke Xu, Lunbiao Cui, Shenjiao Wang, Fei Deng, Xiang Huo, Haodi Huang, Qigang Dai, Changjun Bao
Five epidemic waves of human infection with influenza A (H7N9) virus have emerged in China since spring 2013. We previously described the epidemiological characterization of the fifth wave in Jiangsu province. In this study, 41 H7N9 viruses from patients and live-poultry markets were isolated and sequenced to further elucidate the genetic features of viruses of the fifth wave in Jiangsu province. Phylogenetic analysis revealed substantial genetic diversity in the internal genes, and 18 genotypes were identified from the 41 H7N9 virus strains...
March 14, 2018: Archives of Virology
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Nicholas Calvert, Jiansha Wu, Sophie Sneddon, Jennifer Woodhouse, Richard Carey-Smith, David Wood, Evan Ingley
Background: Soft tissue and bone sarcoma represent a broad spectrum of different pathology and genetic variance. Current chemotherapy regimens are derived from randomised trials and represent empirical treatment. Chemosensitivity testing and whole exome sequencing (WES) may offer personalized chemotherapy treatment based on genetic mutations. Methods: A pilot, prospective, non-randomised control experimental study was conducted. Twelve patients with metastatic bone or soft tissue sarcoma that had failed first line chemotherapy treatment were enrolled for this study...
2018: Clinical Sarcoma Research
Jessada Thutkawkorapin, Hovsep Mahdessian, Tom Barber, Simone Picelli, Susanna von Holst, Johanna Lundin, Laura Valle, Vinaykumar Kontham, Tao Liu, Daniel Nilsson, Xiang Jiao, Annika Lindblom
Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in the region, comparing Swedish CRC cases (2664) and controls (4782)...
February 16, 2018: Oncotarget
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