Literature Watch
Whole exome sequencing in the rat.
Whole exome sequencing in the rat.
BMC Genomics. 2018 Jun 20;19(1):487
Authors: Foley JF, Phadke DP, Hardy O, Hardy S, Miller V, Madan A, Howard K, Kruse K, Lord C, Ramaiahgari S, Solomon GG, Shah RR, Pandiri AR, Herbert RA, Sills RC, Alex Merrick B
Abstract
BACKGROUND: The rat genome was sequenced in 2004 with the aim to improve human health altered by disease and environmental influences through gene discovery and animal model validation. Here, we report development and testing of a probe set for whole exome sequencing (WES) to detect sequence variants in exons and UTRs of the rat genome. Using an in-silico approach, we designed probes targeting the rat exome and compared captured mutations in cancer-related genes from four chemically induced rat tumor cell lines (C6, FAT7, DSL-6A/C1, NBTII) to validated cancer genes in the human database, Catalogue of Somatic Mutations in Cancer (COSMIC) as well as normal rat DNA. Paired, fresh frozen (FF) and formalin-fixed, paraffin-embedded (FFPE) liver tissue from naive rats were sequenced to confirm known dbSNP variants and identify any additional variants.
RESULTS: Informatics analysis of available gene annotation from rat RGSC6.0/rn6 RefSeq and Ensembl transcripts provided 223,636 unique exons representing a total of 26,365 unique genes and untranslated regions. Using this annotation and the Rn6 reference genome, an in-silico probe design generated 826,878 probe sequences of which 94.2% were uniquely aligned to the rat genome without mismatches. Further informatics analysis revealed 25,249 genes (95.8%) covered by at least one probe and 23,603 genes (93.5%) had every exon covered by one or more probes. We report high performance metrics from exome sequencing of our probe set and Sanger validation of annotated, highly relevant, cancer gene mutations as cataloged in the human COSMIC database, in addition to several exonic variants in cancer-related genes.
CONCLUSIONS: An in-silico probe set was designed to enrich the rat exome from isolated DNA. The platform was tested on rat tumor cell lines and normal FF and FFPE liver tissue. The method effectively captured target exome regions in the test DNA samples with exceptional sensitivity and specificity to obtain reliable sequencing data representing variants that are likely chemically induced somatic mutations. Genomic discovery conducted by means of high throughput WES queries should benefit investigators in discovering rat genomic variants in disease etiology and in furthering human translational research.
PMID: 29925311 [PubMed - in process]
Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities.
Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities.
Am J Med Genet A. 2018 Jan;176(1):107-115
Authors: Xiao B, Qiu W, Ji X, Liu X, Huang Z, Liu H, Fan Y, Xu Y, Liu Y, Yie H, Wei W, Yan H, Gong Z, Shen L, Sun Y
Abstract
The diagnosis of intellectual disability/developmental delay (ID/DD) benefits from the clinical application of target/exome sequencing. The yield in Mendelian diseases varies from 25% to 68%. The aim of the present study was to identify the genetic causes of 33 ID/DD patients using target/exome sequencing. Recent studies have demonstrated that reanalyzing undiagnosed exomes could yield additional diagnosis. Therefore, in addition to the normal data analysis, in this study, re-evaluation was performed prior to manuscript preparation after updating OMIM annotations, calling copy number variations (CNVs) and reviewing the current literature. Molecular diagnosis was obtained for 19/33 patients in the first round of analysis. Notably, five patients were diagnosed during the re-evaluation of the geno/phenotypic data. This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re-evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next-generation sequencing (NGS), periodical re-evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re-contacting patients.
PMID: 29159939 [PubMed - indexed for MEDLINE]
Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly.
Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly.
Am J Med Genet A. 2018 Jan;176(1):34-40
Authors: Kar A, Phadke SR, Das Bhowmik A, Dalal A
Abstract
Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome phenotype (JS30), elucidates the genetic heterogeneity of Joubert syndrome, and expands the gene list for ciliopathies.
PMID: 29159890 [PubMed - indexed for MEDLINE]
Expanding the neurodevelopmental phenotype of PURA syndrome.
Expanding the neurodevelopmental phenotype of PURA syndrome.
Am J Med Genet A. 2018 Jan;176(1):56-67
Authors: Lee BH, Reijnders MRF, Abubakare O, Tuttle E, Lape B, Minks KQ, Stodgell C, Bennetto L, Kwon J, Fong CT, Gripp KW, Marsh ED, Smith WE, Huq AM, Coury SA, Tan WH, Solis O, Mehta RI, Leventer RJ, Baralle D, Hunt D, Paciorkowski AR
Abstract
PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations.
PMID: 29150892 [PubMed - indexed for MEDLINE]
Updated strategies for the management, pathogenesis and molecular genetics of different forms of ichthyosis syndromes with prominent hair abnormalities.
Updated strategies for the management, pathogenesis and molecular genetics of different forms of ichthyosis syndromes with prominent hair abnormalities.
Arch Dermatol Res. 2017 Dec;309(10):773-785
Authors: Rasheed M, Shahzad S, Zaeem A, Afzal I, Gul A, Khalid S
Abstract
Syndromic ichthyosis is rare inherited disorders of cornification with varied disease complications. This disorder appears in seventeen subtypes associated with severe systematic manifestations along with medical, cosmetic and social problems. Syndromic ichthyosis with prominent hair abnormalities covers five major subtypes: Netherton syndrome, trichothiodystrophy, ichthyosis hypotrichosis syndrome, ichthyosis hypotrichosis sclerosing cholangitis and ichthyosis follicularis atrichia photophobia syndrome. These syndromes mostly prevail in high consanguinity states, with distinctive clinical features. The known pathogenic molecules involved in ichthyosis syndromes with prominent hair abnormalities include SPINK5, ERCC2, ERCC3, GTF2H5, MPLKIP, ST14, CLDN1 and MBTPS2. Despite underlying genetic origin, most of the health professionals solely rely on phenotypic expression of these disorders that leads to improper management of patients, hence making these patients living an orphanage life. After dermal features, association of other systems such as nervous system, skeletal system, hair abnormalities or liver problems may sometimes give clues for diagnosis but still leaving place for molecular screening for efficient diagnosis. In this paper, we have presented a review of ichthyosis syndrome with prominent hair abnormalities, with special emphasis on their updated genetic consequences and disease management. Additionally, we aim to update health professionals about the practice of molecular screening in ichthyosis syndromes for appropriate diagnosis and treatment.
PMID: 28913623 [PubMed - indexed for MEDLINE]
The HHID syndrome of hypertrichosis, hyperkeratosis, abnormal corpus callosum, intellectual disability, and minor anomalies is caused by mutations in ARID1B.
The HHID syndrome of hypertrichosis, hyperkeratosis, abnormal corpus callosum, intellectual disability, and minor anomalies is caused by mutations in ARID1B.
Am J Med Genet A. 2017 May;173(5):1440-1443
Authors: Zweier M, Peippo MM, Pöyhönen M, Kääriäinen H, Begemann A, Joset P, Oneda B, Rauch A
PMID: 28323383 [PubMed - indexed for MEDLINE]
Notice to Extend the Expiration Date for PAR-18-179 "Research on Informal and Formal Caregiving for Alzheimer's Disease (R21 Clinical Trial Optional)"
Notice to Extend the Expiration Date for PAR-18-027 "Research on Informal and Formal Caregiving for Alzheimer's Disease (R01 Clinical Trial Optional)"
High-Priority Behavioral and Social Research Networks (R24 Clinical Trial Not Allowed)
High-Priority Behavioral and Social Research Networks in Alzheimer's Disease and Alzheimer's Disease Related Dementias (R24 Clinical Trial Not Allowed)
"Rare Diseases"[Mesh] OR "orphan disease"; +23 new citations
23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
"Rare Diseases"[Mesh] OR "orphan disease"
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"systems biology"; +43 new citations
43 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/06/21
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects"); +18 new citations
18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")
These pubmed results were generated on 2018/06/21
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Request for Information (RFI): Evaluation of the NIH Senator Paul D. Wellstone Muscular Dystrophy Research Centers Program
DeCoST: A New Approach in Drug Repurposing From Control System Theory.
DeCoST: A New Approach in Drug Repurposing From Control System Theory.
Front Pharmacol. 2018;9:583
Authors: Nguyen TM, Muhammad SA, Ibrahim S, Ma L, Guo J, Bai B, Zeng B
Abstract
In this paper, we propose DeCoST (Drug Repurposing from Control System Theory) framework to apply control system paradigm for drug repurposing purpose. Drug repurposing has become one of the most active areas in pharmacology since the last decade. Compared to traditional drug development, drug repurposing may provide more systematic and significantly less expensive approaches in discovering new treatments for complex diseases. Although drug repurposing techniques rapidly evolve from "one: disease-gene-drug" to "multi: gene, dru" and from "lazy guilt-by-association" to "systematic model-based pattern matching," mathematical system and control paradigm has not been widely applied to model the system biology connectivity among drugs, genes, and diseases. In this paradigm, our DeCoST framework, which is among the earliest approaches in drug repurposing with control theory paradigm, applies biological and pharmaceutical knowledge to quantify rich connective data sources among drugs, genes, and diseases to construct disease-specific mathematical model. We use linear-quadratic regulator control technique to assess the therapeutic effect of a drug in disease-specific treatment. DeCoST framework could classify between FDA-approved drugs and rejected/withdrawn drug, which is the foundation to apply DeCoST in recommending potentially new treatment. Applying DeCoST in Breast Cancer and Bladder Cancer, we reprofiled 8 promising candidate drugs for Breast Cancer ER+ (Erbitux, Flutamide, etc.), 2 drugs for Breast Cancer ER- (Daunorubicin and Donepezil) and 10 drugs for Bladder Cancer repurposing (Zafirlukast, Tenofovir, etc.).
PMID: 29922160 [PubMed]
Fat label compared with fat content: gastrointestinal symptoms and brain activity in functional dyspepsia patients and healthy controls.
Fat label compared with fat content: gastrointestinal symptoms and brain activity in functional dyspepsia patients and healthy controls.
Am J Clin Nutr. 2018 Jun 18;:
Authors: Lee IS, Kullmann S, Scheffler K, Preissl H, Enck P
Abstract
Background: High-fat meals are associated with dyspeptic symptoms in functional dyspepsia (FD) patients. It is still unclear how fat is processed, or how FD symptoms and neuronal activities are modulated by psychological factors.
Objective: We investigated brain activity by functional magnetic resonance imaging (fMRI) after the ingestion of high- and low-fat foods with correct/incorrect fat information.
Design: We compared 12 FD patients and 14 healthy controls (HCs). We recorded resting-state fMRI on four different days before and after ingestion of four yogurts (200 mL, 10% or 0.1% fat, "low fat" or "high fat" label).
Results: FD patients showed more pronounced dyspeptic symptoms than did HCs, and symptoms were relieved less after consuming high fat-labeled yogurt than low fat-labeled yogurt, irrespective of the actual fat content. This is indicative of either a placebo effect of low-fat information or a nocebo effect of high-fat information on symptom expression. FD patients showed greater activity than did HCs in occipital areas before and after ingestion regardless of fat content and label, as well as greater activity in the middle frontal gyrus before ingestion. In addition, functional connectivity (FC) from the insula to the occipital cortex (I-O) increased after high fat ingestion and decreased after low fat ingestion in FD patients. FC from the insula to the precuneus (I-P) was higher in FD patients than in HCs after ingestion of low fat-labeled yogurt. In FD patients, I-O FC negatively correlated with nausea and I-P FC with FD symptom intensity, food craving, and depression.
Conclusions: Our results endorse the importance of psychological perception of food on the incidence of dyspeptic symptoms and on the altered brain activities. These findings show the importance of cognitive components in perceptions of fat, food craving, depression, and brain functions in pathophysiologic mechanisms of FD. This trial was registered at clinicaltrials.gov as NCT02618070.
PMID: 29924294 [PubMed - as supplied by publisher]
NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.
NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.
J Gastroenterol. 2018 Jun 19;:
Authors: Kakuta Y, Kawai Y, Okamoto D, Takagawa T, Ikeya K, Sakuraba H, Nishida A, Nakagawa S, Miura M, Toyonaga T, Onodera K, Shinozaki M, Ishiguro Y, Mizuno S, Takahara M, Yanai S, Hokari R, Nakagawa T, Araki H, Motoya S, Naito T, Moroi R, Shiga H, Endo K, Kobayashi T, Naganuma M, Hiraoka S, Matsumoto T, Nakamura S, Nakase H, Hisamatsu T, Sasaki M, Hanai H, Andoh A, Nagasaki M, Kinouchi Y, Shimosegawa T, Masamune A, Suzuki Y, MENDEL study group
Abstract
BACKGROUND: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.
METHODS: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.
RESULTS: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).
CONCLUSIONS: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.
PMID: 29923122 [PubMed - as supplied by publisher]
Application of pharmacogenetics in clinical practice: problems and solutions.
Application of pharmacogenetics in clinical practice: problems and solutions.
J Neural Transm (Vienna). 2018 Jun 19;:
Authors: Baskys A
Abstract
This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.
PMID: 29922908 [PubMed - as supplied by publisher]
Characterization CYP1A2, CYP2C9, CYP2C19 and CYP2D6 polymorphisms using HRMA in Psychiatry patients with schizophrenia and bipolar disease for personalized medicine.
Characterization CYP1A2, CYP2C9, CYP2C19 and CYP2D6 polymorphisms using HRMA in Psychiatry patients with schizophrenia and bipolar disease for personalized medicine.
Comb Chem High Throughput Screen. 2018 Jun 19;:
Authors: Yenilmez ED, Tamam L, Karaytug O, Tuli A
Abstract
BACKGROUND: The interindividual genetic variations in drug metabolizing enzymes effects the impact and toxicity in plenty of drugs.
OBJECTIVE: The CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene polymorphisms characterized using high resolution melting analysis (HRMA) in follow-up patients in psychiatry clinic as a preliminary preparation for personalized medicine.
METHOD: Genotyping of CYP1A2*1F, CYP2C9 *2, *3, CYP2C19 *2, *3 and *17 and CYP2D6 *3, *4 was conducted in 101 patients using HRMA. Genotype and allele frequencies of the CYP variants were found to be in equilibrium with the Hardy-Weinberg equation.
RESULTS: The frequency of the CYP1A2*1F allele in schizophrenia and bipolar disease was 0.694 and 0.255, respectively. The CYP2C9 allele frequencies were 0.087 (CYP2C9*2), and 0.549 (CYP2C9*3) for bipolar; 0.278 (CYP2C9*2) and 0.648 (CYP2C9*3) in schizophrenias. The CYP2C19*2 and *17 allele frequencies was 0.111 and 0.185 in schizophrenia and variant *2 was 0.117 and variant *17 was 0.255 in bipolar group. The frequency of the CYP2D6*3 allele was 0.027 in schizophrenias. The frequencies for the CYP2D6*4 variant was 0.092 and 0.096 in schizophrenia and bipolar groups, respectively.
CONCLUSION: The knowledge in pharmacogenomics and also the developments in molecular genetics are growing rapidly. In the future this can be expected to provide new methodologies in the prediction of the activity in drug metabolizing enzymes. The HRMA is a rapid and useful technique to identify the genotypes for drug dosage adjustment before therapy in psychiatry patients.
PMID: 29921201 [PubMed - as supplied by publisher]
Extranodal extension of nodal metastases is a poor prognostic moderator in non-small cell lung cancer: a meta-analysis.
Extranodal extension of nodal metastases is a poor prognostic moderator in non-small cell lung cancer: a meta-analysis.
Virchows Arch. 2018 Jun;472(6):939-947
Authors: Luchini C, Veronese N, Nottegar A, Cheng M, Kaneko T, Pilati C, Tabbò F, Stubbs B, Pea A, Bagante F, Demurtas J, Fassan M, Infante M, Cheng L, Scarpa A
Abstract
Extranodal extension (ENE) of nodal metastasis is defined as the extension of metastatic cells through the nodal capsule into the perinodal tissue. This morphological parameter, recently proposed as an important prognostic factor in different types of malignancy, has not been included in the TNM staging system for non-small cell lung cancer (NSCLC). In this systematic review with meta-analysis, we weighted the prognostic role of ENE in patients with lymph node-positive NSCLC. Two independent authors searched SCOPUS and PubMed through 28 February 2017. Prospective and retrospective studies on NSCLC, comparing patients with presence of ENE (ENE+) ENE+) vs. only intranodal extension (ENE-) and including data regarding prognosis, were considered as eligible. Data were summarized using risk ratios (RR) for the number of deaths/recurrences, and hazard ratios (HR) with 95% confidence intervals (CI) for time-dependent risk related to ENE+, adjusted for potential confounders. We identified 13 studies, including 1709 patients (573 ENE+ and 1136 ENE-) with a median follow-up of 60 months. ENE was associated with a significantly increased risk of mortality of all causes (RR = 1.39, 95% CI: 1.18-1.65, P < 0.0001, I2 = 70%; HR = 1.30, 95% CI: 1.01-1.67, P = 0.04, I2 = 0%) and of disease recurrence (RR = 1.32, 95% CI: 1.04-1.68, P = 0.02, I2 = 42%; HR = 1.93, 95% CI: 1.53-2.44, P < 0.0001, I2 = 0%). We conclude that in NSCLC, requirements for assessment of ENE should be included in gross sampling and ENE status should be included in the pathology report. Inclusion of ENE status in oncology staging systems will allow further assessment of its role as prognostic parameter.
PMID: 29392400 [PubMed - indexed for MEDLINE]
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