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Mendelian disease

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https://www.readbyqxmd.com/read/28714989/correction-of-a-splicing-defect-in-a-mouse-model-of-congenital-muscular-dystrophy-type-1a-using-a-homology-directed-repair-independent-mechanism
#1
Dwi U Kemaladewi, Eleonora Maino, Elzbieta Hyatt, Huayun Hou, Maylynn Ding, Kara M Place, Xinyi Zhu, Prabhpreet Bassi, Zahra Baghestani, Amit G Deshwar, Daniele Merico, Hui Y Xiong, Brendan J Frey, Michael D Wilson, Evgueni A Ivakine, Ronald D Cohn
Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation...
July 17, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28714225/leveraging-splice-affecting-variant-predictors-and-a-minigene-validation-system-to-identify-mendelian-disease-causing-variants-amongst-exon-captured-variants-of-uncertain-significance
#2
Zachry T Soens, Justin Branch, Shijing Wu, Zhisheng Yuan, Yumei Li, Hui Li, Keqing Wang, Mingchu Xu, Lavan Rajan, Fabiana L Motta, Renata T Simões, Irma Lopez-Solache, Radwan Ajlan, David G Birch, Peiquan Zhao, Fernanda B Porto, Juliana Sallum, Robert K Koenekoop, Ruifang Sui, Rui Chen
The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS's) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation...
July 17, 2017: Human Mutation
https://www.readbyqxmd.com/read/28712454/crispr-cas9-mediated-scanning-for-regulatory-elements-required-for-hprt1-expression-via-thousands-of-large-programmed-genomic-deletions
#3
Molly Gasperini, Gregory M Findlay, Aaron McKenna, Jennifer H Milbank, Choli Lee, Melissa D Zhang, Darren A Cusanovich, Jay Shendure
The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder...
July 1, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28702714/immunodeficiency-in-two-female-patients-with-incontinentia-pigmenti-with-heterozygous-nemo-mutation-diagnosed-by-lps-unresponsiveness
#4
Hidenori Ohnishi, Yuka Kishimoto, Tomohide Taguchi, Norio Kawamoto, Mina Nakama, Tomoki Kawai, Manabu Nakayama, Osamu Ohara, Kenji Orii, Toshiyuki Fukao
PURPOSE: Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is caused by mutations in the NF-κB essential modulator (NEMO) or NF-κB inhibitor, alpha (IKBA) genes. A heterozygous NEMO mutation causes incontinentia pigmenti (IP) in females, while a hemizygous hypomorphic mutation of NEMO causes EDA-ID in males. In general, immunodeficiency is not shown in IP patients. Here, we investigated two female patients with IP and immunodeficiency. METHODS: The patients were initially suspected to have IRAK4 deficiency and Mendelian susceptibility to mycobacterial disease, respectively, because of recurrent pneumonia with delayed umbilical cord detachment or disseminated mycobacterial infectious disease...
July 12, 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/28701353/known-and-unknowns-in-the-care-of-paediatric-familial-hypercholesterolaemia
#5
Andrew C Martin, Samuel S Gidding, Albert Wiegman, Gerald F Watts
Familial hypercholesterolaemia (FH) is a common genetic disorder that causes elevated low-density lipoprotein (LDL)-cholesterol levels from birth. Untreated FH accelerates atherosclerosis and predisposes individuals to premature coronary artery disease (CAD) in adulthood. Mendelian randomization studies have demonstrated that LDL-cholesterol has both a causal and cumulative effect on the risk of CAD. This supports clinical recommendations that children with FH commence pharmacological treatment from age 8-10 years, to reduce the burden of hypercholesterolaemia...
July 12, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28700664/systematic-screening-for-skin-hair-and-nail-abnormalities-in-a-large-scale-knockout-mouse-program
#6
John P Sundberg, Soheil S Dadras, Kathleen A Silva, Victoria E Kennedy, Gaven Garland, Stephen A Murray, Beth A Sundberg, Paul N Schofield, C Herbert Pratt
The International Knockout Mouse Consortium was formed in 2007 to inactivate ("knockout") all protein-coding genes in the mouse genome in embryonic stem cells. Production and characterization of these mice, now underway, has generated and phenotyped 3,100 strains with knockout alleles. Skin and adnexa diseases are best defined at the gross clinical level and by histopathology. Representative retired breeders had skin collected from the back, abdomen, eyelids, muzzle, ears, tail, and lower limbs including the nails...
2017: PloS One
https://www.readbyqxmd.com/read/28684688/gene-dairy-food-interactions-and-health-outcomes-a-review-of-nutrigenetic-studies
#7
REVIEW
Kevin B Comerford, Gonca Pasin
Each person differs from the next by an average of over 3 million genetic variations in their DNA. This genetic diversity is responsible for many of the interindividual differences in food preferences, nutritional needs, and dietary responses between humans. The field of nutrigenetics aims to utilize this type of genetic information in order to personalize diets for optimal health. One of the most well-studied genetic variants affecting human dietary patterns and health is the lactase persistence mutation, which enables an individual to digest milk sugar into adulthood...
July 6, 2017: Nutrients
https://www.readbyqxmd.com/read/28684612/the-effect-of-iron-status-on-risk-of-coronary-artery-disease-a-mendelian-randomization-study
#8
Dipender Gill, Fabiola Del Greco M, Ann P Walker, Surjit K S Srai, Michael A Laffan, Cosetta Minelli
OBJECTIVE: Iron status is a modifiable trait that has been implicated in cardiovascular disease. This study uses the Mendelian randomization technique to investigate whether there is any causal effect of iron status on risk of coronary artery disease (CAD). APPROACH AND RESULTS: A 2-sample Mendelian randomization approach is used to estimate the effect of iron status on CAD risk. Three loci (rs1800562 and rs1799945 in the HFE gene and rs855791 in TMPRSS6) that are each associated with serum iron, transferrin saturation, ferritin, and transferrin in a pattern suggestive of an association with systemic iron status are used as instruments...
July 6, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28684198/flow-cytometry-based-diagnosis-of-primary-immunodeficiency-diseases
#9
REVIEW
Hirokazu Kanegane, Akihiro Hoshino, Tsubasa Okano, Takahiro Yasumi, Taizo Wada, Hidetoshi Takada, Satoshi Okada, Motoi Yamashita, Tzu-Wen Yeh, Ryuta Nishikomori, Masatoshi Takagi, Kohsuke Imai, Hans D Ochs, Tomohiro Morio
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs...
July 3, 2017: Allergology International: Official Journal of the Japanese Society of Allergology
https://www.readbyqxmd.com/read/28684086/modifier-genes-moving-from-pathogenesis-to-therapy
#10
Edward R B McCabe
This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms...
May 30, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28679849/mendelian-genes-and-risk-of-intracerebral-hemorrhage-and-small-vessel-ischemic-stroke-in-sporadic-cases
#11
Michael Chong, Martin O'Donnell, Vincent Thijs, Antonio Dans, Patricio López-Jaramillo, Diego Gómez-Arbeláez, Charles Mondo, Anna Czlonkowska, Marta Skowronska, Shahram Oveisgharan, Salim Yusuf, Guillaume Paré
BACKGROUND AND PURPOSE: Mendelian strokes are rare genetic disorders characterized by early-onset small-vessel stroke. Although extensively studied among families with syndromic features, whether these genes affect risk among sporadic cases is unknown. METHODS: We sequenced 8 genes responsible for Mendelian stroke in a case-control study of sporadic stroke cases (≤70 years). Participants included 1251 primary stroke cases of small-vessel pathology (637 intracerebral hemorrhage and 614 small-vessel ischemic stroke cases) and 1716 controls from the INTERSTROKE study (Study of the Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World)...
July 5, 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/28678979/association-of-body-mass-index-with-cardiometabolic-disease-in-the-uk-biobank-a-mendelian-randomization-study
#12
Donald M Lyall, Carlos Celis-Morales, Joey Ward, Stamatina Iliodromiti, Jana J Anderson, Jason M R Gill, Daniel J Smith, Uduakobong Efanga Ntuk, Daniel F Mackay, Michael V Holmes, Naveed Sattar, Jill P Pell
Importance: Higher body mass index (BMI) is a risk factor for cardiometabolic disease; however, the underlying causal associations remain unclear. Objectives: To use UK Biobank data to report causal estimates of the association between BMI and cardiometabolic disease outcomes and traits, such as pulse rate, using mendelian randomization. Design, Setting, and Participants: Cross-sectional baseline data from a population-based cohort study including 119 859 UK Biobank participants with complete phenotypic (medical and sociodemographic) and genetic data...
July 5, 2017: JAMA Cardiology
https://www.readbyqxmd.com/read/28674994/gene-linkage-and-systems-biology
#13
Mark R Cookson
In the past two decades it has become increasingly clear that the risk for many neurodegenerative disorders is at least partially genetic. Assignment of causality for a given gene depends on showing that a particular variant shows either segregation within a family or association with disease across a population. In terms of lifetime risk of disease, the former generally show strong effects compared to the latter. In rare, but interesting, circumstances there are genetic loci that contain different variants that encode either highly penetrant Mendelian disease but also that contribute to risk of sporadic disease...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28669352/impact-of-comorbidities-on-gout-and-hyperuricaemia-an-update-on-prevalence-and-treatment-options
#14
REVIEW
Thomas Bardin, Pascal Richette
Gout, the most prevalent inflammatory arthritis worldwide, is associated with cardiovascular and renal diseases, and is an independent predictor of premature death. The frequencies of obesity, chronic kidney disease (CKD), hypertension, type 2 diabetes, dyslipidaemias, cardiac diseases (including coronary heart disease, heart failure and atrial fibrillation), stroke and peripheral arterial disease have been repeatedly shown to be increased in gout. Therefore, the screening and care of these comorbidities as well as of cardiovascular risk factors are of outmost importance in patients with gout...
July 3, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28663792/recent-advances-in-congenital-heart-disease-genomics
#15
REVIEW
Anna Wilsdon, Alejandro Sifrim, Marc-Phillip Hitz, Matthew Hurles, J David Brook
Congenital heart disease is the most common congenital abnormality, and advances in medical care mean that this population of individuals is surviving for longer than ever before. It represents a significant healthcare challenge, as many patients require life-long care and individuals may ask about the likelihood of their children being affected. Whilst a number of genes have been identified previously from investigation of families with Mendelian inheritance patterns, sequencing the DNA from large cohorts of individuals with congenital heart disease is now providing fresh insights into the genetics of these conditions...
2017: F1000Research
https://www.readbyqxmd.com/read/28663202/low-ldl-cholesterol-pcsk9-and-hmgcr-genetic-variation-and-risk-of-alzheimer-s-disease-and-parkinson-s-disease-mendelian-randomisation-study
#16
(no author information available yet)
No abstract text is available yet for this article.
June 29, 2017: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/28659270/fifteen-years-of-genetic-testing-from-a-london-developmental-clinic
#17
Sunayna Best, Elisabeth Rosser, Monika Bajaj
OBJECTIVE: To evaluate genetic disease among children referred to a community paediatric clinic. DESIGN: Retrospective cohort study. SETTING: Community paediatric clinic, Tower Hamlets, London. PATIENTS: All patients seen for first time in the Child Development Team (CDT) clinic between 1999 and 2013. INTERVENTIONS: Clinical notes were reviewed. Genetic test results were obtained. Exploratory Excel analysis was performed...
June 28, 2017: Archives of Disease in Childhood
https://www.readbyqxmd.com/read/28655553/variant-discovery-in-patients-with-mendelian-vascular-anomalies-by-next-generation-sequencing-and-their-use-in%C3%A2-patient-clinical-management
#18
Raul Mattassi, Elena Manara, Pier Giuseppe Colombo, Sofia Manara, Antonella Porcella, Giulia Bruno, Alice Bruson, Matteo Bertelli
OBJECTIVE: An accurate "molecular" diagnosis and classification of similar but distinct diseases is sometime challenging but often crucial for the definition of the appropriate patient medical management and treatment as well as for genetic counseling and risk assessment in families. The advent of next-generation sequencing (NGS), which analysed all known disease-associated genes in parallel in a cost- and time-effective manner, eased this process of disease definition and also for vascular anomalies that are a heterogeneous group of vascular tumors and congenital circulatory malformations and often characterized by overlapping phenotypes...
June 24, 2017: Journal of Vascular Surgery
https://www.readbyqxmd.com/read/28654958/the-impact-of-whole-genome-sequencing-on-the-primary-care-and-outcomes-of-healthy-adult-patients-a-pilot-randomized-trial
#19
Jason L Vassy, Kurt D Christensen, Erica F Schonman, Carrie L Blout, Jill O Robinson, Joel B Krier, Pamela M Diamond, Matthew Lebo, Kalotina Machini, Danielle R Azzariti, Dmitry Dukhovny, David W Bates, Calum A MacRae, Michael F Murray, Heidi L Rehm, Amy L McGuire, Robert C Green
Background: Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value. Objective: To describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care. Design: Pilot randomized trial. (ClinicalTrials.gov: NCT01736566). Setting: Academic primary care practices. Participants: 9 primary care physicians (PCPs) and 100 generally healthy patients recruited at ages 40 to 65 years...
June 27, 2017: Annals of Internal Medicine
https://www.readbyqxmd.com/read/28645180/alcohol-metabolism-and-oesophageal-cancer-a-systematic-review-of-the-evidence
#20
Marco Matejcic, M J Gunter, Pietro Ferrari
Alcohol is a major risk factor for oesophageal squamous cell carcinoma (OSCC), the most prevalent histological subtype of oesophageal cancer (OC) worldwide. The metabolism of alcohol is regulated by specific enzymes whose activity and expression is influenced by genetic polymorphisms. We conducted a systematic review of current epidemiological evidence of the relationship between alcohol intake and OC risk, including the role of tobacco smoking and functional polymorphisms of dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs)...
June 22, 2017: Carcinogenesis
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