Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway.

Sci Rep. 2017 Apr 19;7:46454

Authors: Andreoletti G, Shakhnovich V, Christenson K, Coelho T, Haggarty R, Afzal NA, Batra A, Petersen BS, Mort M, Beattie RM, Ennis S

Abstract
Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort (BIRC2 p = 0.004, NFKB1 p =  0.005, NOD2 p = 0.029 and SUGT1 p = 0.047). Statistical significance was replicated for BIRC2 (p = 0.041) and NOD2 (p = 0.045) in an independent validation cohort. A gene based test on the combined discovery and replication cohort confirmed association for BIRC2 (p = 0.030). We successfully applied burden of mutation testing that jointly assesses common and rare variants, identifying two previously implicated genes (NFKB1 and NOD2) and confirmed a possible role in disease risk in a previously unreported gene (BIRC2). The identification of this novel gene provides a wider role for the inhibitor of apoptosis gene family in IBD pathogenesis.

PMID: 28422189 [PubMed - in process]

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Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations.

Front Immunol. 2017;8:344

Authors: Martorana D, Bonatti F, Mozzoni P, Vaglio A, Percesepe A

Abstract
Autoinflammatory diseases (AIDs) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins, which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AIDs, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AIDs are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes. During the last years, remarkable progress has been made in the identification of disease-associated genes by using new technologies, such as next-generation sequencing, which has allowed the genetic characterization in undiagnosed patients and in sporadic cases by means of targeted resequencing of a gene panel and whole exome sequencing. In this review, we delineate the genetics of the monogenic AIDs, report the role of the most common gene mutations, and describe the evidences of the most sound genotype/phenotype correlations in AID.

PMID: 28421071 [PubMed - in process]

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Application and progress of high-throughput sequencing technologies in the research of hereditary hearing loss.

Yi Chuan. 2017 Mar 20;39(3):208-219

Authors: Cuicui W, Huijun Y

Abstract
Hearing loss (HL) is the most common birth defect. Elucidating the genetic basis of hereditary deafness can not only assist diagnosis, provide the basis for genetic counseling and the prevention of deafness, but also bring a deeper understanding of the disease pathogenesis. In the genomic era, high-throughput sequencing technologies, represented by whole genome sequencing (WGS), whole exome sequencing (WES) or target region sequencing, have been widely used in the studies of hereditary HL. Here, we summarize the application and progress of WES and target region sequencing in the research of causative genes and clinical molecular diagnosis of hereditary HL, hoping to be helpful for the development and improvement of clinical genetic diagnosis of deafness in China.

PMID: 28420617 [PubMed - in process]

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Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

Genome Med. 2017 Apr 19;9(1):34

Authors: Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, Huang F, He Y, Sun J, Tabori U, Kennedy M, Lieber DS, Roels S, White J, Otto GA, Ross JS, Garraway L, Miller VA, Stephens PJ, Frampton GM

Abstract
BACKGROUND: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.
METHODS: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types.
RESULTS: We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB.
CONCLUSIONS: These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.

PMID: 28420421 [PubMed - in process]

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Novel Genetic Variants Associated with Child Refractory Esophageal Stricture with Food Allergy by Exome Sequencing.

Nutrients. 2017 Apr 15;9(4):

Authors: Yang M, Xiong M, Chen H, Geng L, Chen P, Xie J, Ye SQ, Li DY, Gong S

Abstract
BACKGROUND: Refractory esophageal stricture (RES) may be attributed to food allergy. Its etiology and pathogenesis are not fully understood. Identification of novel genetic variants associated with this disease by exome sequencing (exome-seq) may provide new mechanistic insights and new therapeutic targets.
METHODS: To identify new and novel disease-associating variants, whole-exome sequencing was performed on an Illumina NGS platform in three children with RES as well as food allergy.
RESULTS: A total of 91,024 variants were identified. By filtering out 'normal variants' against those of the 1000 Genomes Project, we identified 12,741 remaining variants which are potentially associated with RES plus food allergy. Among these variants, there are 11,539 single nucleotide polymorphisms (SNPs), 627 deletions, 551 insertions and 24 mixture variants. These variants are located in 1370 genes. They are enriched in biological processes or pathways such as cell adhesion, digestion, receptor metabolic process, bile acid transport and the neurological system. By the PubMatrix analysis, 50 out of the top 100 genes, which contain most variants, have not been previously associated with any of the 17 allergy-associated diseases. These 50 genes represent newly identified allergy-associated genes. Those variants of 627 deletions and 551 insertions have also not been reported before in RES with food allergy.
CONCLUSIONS: Exome-seq is potentially a powerful tool to identify potential new biomarkers for RES with food allergy. This study has identified a number of novel genetic variants, opening new avenues of research in RES plus food allergy. Additional validation in larger and different patient populations and further exploration of the underlying molecular mechanisms are warranted.

PMID: 28420126 [PubMed - in process]

Funding Opportunity RFA-RM-17-007 from the NIH Guide for Grants and Contracts. The NIH Director's Transformative Research Award complements NIHs traditional, investigator-initiated grant programs by supporting individual scientists or groups of scientists proposing groundbreaking, exceptionally innovative, original and/or unconventional research with the potential to create new scientific paradigms, establish entirely new and improved clinical approaches, or develop transformative technologies. Little or no preliminary data are expected. Projects must clearly demonstrate the potential to produce a major impact in a broad area of biomedical or behavioral research. The NIH Directors Transformative Research Award is a component of the High-Risk, High-Reward Research program of the NIH Common Fund.

Funding Opportunity PA-17-261 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites R18 grant applications for developing new clinical decision support (CDS) to facilitate the dissemination and implementation of evidence-based research findings. The purposes of this FOA are to develop new, reliable, valid, and usable CDS from evidence-based research findings and then demonstrate its effectiveness to improve care in clinical practice.

Funding Opportunity PA-17-260 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites R18 grant applications for research projects to scale and spread existing clinical decision support (CDS) to facilitate the dissemination and implementation of evidence-based research findings into clinical practice. The purposes of this FOA are to extend the implementation ("scale") and evaluation of well-established and effective CDS beyond the initial clinical setting or institution in which the CDS was originally developed and implemented, thereby extending the impact on clinical practice.

Funding Opportunity RFA-RM-17-005 from the NIH Guide for Grants and Contracts. The NIH Directors Pioneer Award complements NIH's traditional, investigator-initiated grant programs by supporting individual scientists of exceptional creativity who propose pioneering and possibly transforming approaches to addressing major biomedical or behavioral challenges that have the potential to produce an unusually high impact on enhancing health, lengthening life, and reducing illness and disability. To be considered pioneering, the proposed research must reflect substantially different scientific directions from those already being pursued in the investigators research program or elsewhere. The NIH Directors Pioneer Award is a component of the High-Risk, High-Reward Research program of the NIH Common Fund.

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Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice.

Psychopharmacology (Berl). 2017 Apr 18;:

Authors: Montalvo-Ortiz JL, Fisher DW, Rodríguez G, Fang D, Csernansky JG, Dong H

Abstract
BACKGROUND: Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility.
METHODS: In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL.
RESULTS: Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone tri-methylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter.
CONCLUSIONS: These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.

PMID: 28421257 [PubMed - as supplied by publisher]

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Primary Cutaneous Aspergillosis in a Preterm Infant.

Pediatr Infect Dis J. 2016 Jun;35(6):704-6

Authors: Frick MA, Boix H, Camba Longueira F, Martin-Gomez MT, Rodrigo-Pendás JÁ, Soler-Palacin P

Abstract
Primary cutaneous aspergillosis is rare in premature infants. It requires combined medical and surgical strategies. Liposomal amphotericin B is recommended as first-line therapy, but salvage regimens with others antifungal agents, such as voriconazole, have been reported. Voriconazole's pharmacodynamics is unknown in this population. We report a case of severe toxicity to voriconazole in a preterm patient with primary cutaneous aspergillosis.

PMID: 26974892 [PubMed - indexed for MEDLINE]

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Sofosbuvir and Simeprevir Treatment of a Stem Cell Transplanted Teenager With Chronic Hepatitis C Infection.

Pediatr Infect Dis J. 2016 Jun;35(6):708-10

Authors: Fischler B, Priftakis P, Sundin M

Abstract
There have been no previous reports on the use of interferon-free combinations in pediatric patients with chronic hepatitis C infection. An infected adolescent with severe sickle cell disease underwent stem cell transplantation and subsequent treatment with sofosbuvir and simeprevir during ongoing immunosuppression. Despite the emergence of peripheral edema as a side effect, treatment was continued with sustained antiviral response.

PMID: 26928522 [PubMed - indexed for MEDLINE]

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Five-year Antibody Persistence and Booster Response After 1 or 2 Doses of Meningococcal A, C, W and Y Tetanus Toxoid Conjugate Vaccine in Healthy Children.

Pediatr Infect Dis J. 2016 06;35(6):662-72

Authors: Klein NP, Baine Y, Kolhe D, Baccarini CI, Miller JM, Van der Wielen M

Abstract
BACKGROUND: We evaluated antibody persistence up to 5 years postvaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT), and subsequent booster responses to MenACWY-TT in healthy US children.
METHODS: In the initial phase II, open, multicenter study (NCT00471081), 349 infants were randomized (1:1) to receive MenACWY-TT (1 or 2 doses). In the follow-up study (NCT00718666), we evaluated antibody persistence at years 1, 3 and 5 by serum bactericidal assay using human complement (hSBA). At year 5, children received a booster dose of MenACWY-TT. We compared their immune responses at 1 month postbooster with those from 100 age-matched, meningococcal naive children, who received a primary MenACWY-TT dose. We recorded solicited adverse events for 4 days and unsolicited adverse events for 31 days, followed by an additional 5-month extended safety follow-up.
RESULTS: At year 5, ≥64.0% of 1-dose and ≥74.6% of 2-dose recipients had hSBA titers ≥8 for MenC, MenW and MenY. For MenA, 31.7% of 1-dose and 38.0% of 2-dose recipients had hSBA titers ≥8. One month postvaccination, all booster dose recipients and ≥78.5% of primary dose recipients exhibited hSBA titers ≥8 for all serogroups. Geometric mean titers were higher in primed than in naive children. MenACWY-TT had a clinically acceptable safety profile.
CONCLUSIONS: With the exception of serogroup W, antibody persistence 5 years after MenACWY-TT vaccination did not differ substantially between children who received 1 or 2 doses in infancy. A booster dose of MenACWY-TT elicited robust anamnestic responses and was well tolerated.

PMID: 26928521 [PubMed - indexed for MEDLINE]

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Daptomycin for Children in Clinical Practice Experience.

Pediatr Infect Dis J. 2016 06;35(6):639-41

Authors: Garazzino S, Castagnola E, Di Gangi M, Ortolano R, Krzysztofiak A, Nocerino A, Esposito S, D'Argenio P, Galli L, Losurdo G, Calitri C, Tovo PA, SITIP Daptomycin Study Group

Abstract
Data on daptomycin use in the pediatric setting are scanty. We conducted a multicenter, retrospective study on 46 children treated with intravenous daptomycin at a mean dosage of 7.0 mg/kg/d, for a median of 14 days. Three children had adverse events possibly related to daptomycin. The drug was overall well tolerated, even with prolonged treatment.

PMID: 26910590 [PubMed - indexed for MEDLINE]

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Pharmacokinetics, Safety and Tolerability of Single Oral or Intravenous Administration of 200 mg Tedizolid Phosphate in Adolescents.

Pediatr Infect Dis J. 2016 06;35(6):628-33

Authors: Bradley JS, Flanagan SD, Arrieta AC, Jacobs R, Capparelli E, Prokocimer P

Abstract
BACKGROUND: Tedizolid is a novel oxazolidinone antibacterial US FDA approved for treatment of acute bacterial skin and skin structure infections in adults. This study assessed the pharmacokinetics, safety and tolerability of tedizolid phosphate in adolescents (12-17 years old) after administration of a single intravenous (IV) or oral dose.
METHODS: In this multicenter, open-label study, a single IV infusion (N = 10) or oral dose (N = 10) of 200 mg tedizolid phosphate was administered to adolescents already receiving antibacterial treatment for presumed or documented infection. Blood and urine samples were collected predose and over 24 hours.
RESULTS: Tedizolid pharmacokinetics was generally similar after IV or oral administration of 200 mg tedizolid phosphate. Mean (standard deviation) half-life values were similar for oral and IV routes, 8.3 (2.0) and 6.6 (0.7) hours, respectively. Absolute oral bioavailability of tedizolid (90% confidence interval) was 88.8% (70.4%-112.1%). Geometric mean ratio (90% confidence interval) of area under the concentration-time curve values for adolescents relative to values previously reported for adults after 200 mg of single-dose IV or oral administration were 0.847 (0.736-0.975). Tedizolid was well tolerated.
CONCLUSIONS: Overall pharmacokinetics of tedizolid was similar after administration of a single oral or IV 200 mg dose, and bioavailability was high. Exposure profiles were similar to those in adults. With clinical outcomes based on area under the concentration-time curve/minimum inhibitory concentration and current susceptibility of Gram-positive pathogens, results suggest that the 200 mg daily regimen of tedizolid phosphate can be extended to adolescents for clinical trials, and that dose adjustment may not be required when switching routes.

PMID: 26910588 [PubMed - indexed for MEDLINE]

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Treatment of Congenital Toxoplasmosis: Safety of the Sulfadoxine-Pyrimethamine Combination in Children Based on a Method of Causality Assessment.

Pediatr Infect Dis J. 2016 06;35(6):634-8

Authors: Teil J, Dupont D, Charpiat B, Corvaisier S, Vial T, Leboucher G, Wallon M, Peyron F

Abstract
BACKGROUND: The treatment of newborns and infants with congenital toxoplasmosis is standard practice. Some observational studies have examined safety in newborns, but most of these failed to provide sufficient details for a provisional assessment of causality. The aim of this study was to evaluate the clinical and biological adverse effects of the combination of sulfadoxine-pyrimethamine.
METHODS: Sixty-five children treated for 1 year with a combination of sulfadoxine-pyrimethamine (1 dose every 10 days) for congenital toxoplasmosis were followed up to evaluate abnormal hematological values and potential adverse events using a standardized method of causality assessment.
RESULTS: Nine patients (13.8%) presented at least 1 adverse clinical event that was nonspecific, such as diarrhea on the day of drug administration, vomiting and agitation. In 1 patient, erythema appeared at the end of the treatment and resolved within 10 days. None of these events was attributed to the treatment. Six patients (9.2%) developed an adverse hematological event (neutropenia, n = 3; eosinophilia, n = 2 and both anemia and eosinophilia, n = 1) that was considered to be possibly related to the sulfadoxine-pyrimethamine combination. Four treatments were temporarily interrupted, and toxicity was observed after readministration of treatment in 1 case only. However, none of these adverse events was life threatening.
CONCLUSIONS: According to our results and previously published data, the combination of sulfadoxine-pyrimethamine seems to be well tolerated. However, the sample size of our study was too small to rule out the risk of less frequent, but nevertheless severe, reactions and, in particular, of hypersensitivity reactions.

PMID: 26906163 [PubMed - indexed for MEDLINE]

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Linezolid is Associated with Improved Early Outcomes of Childhood Tuberculous Meningitis.

Pediatr Infect Dis J. 2016 06;35(6):607-10

Authors: Li H, Lu J, Liu J, Zhao Y, Ni X, Zhao S

Abstract
BACKGROUND: Linezolid serves as an important component for the treatment of drug-resistant tuberculosis although there is little published data about linezolid use in children, especially in childhood tuberculous meningitis (TBM).
METHODS: In this study, we retrospectively reviewed records of childhood TBM patients who started treatment between January 2012 and August 2014. A total of 86 childhood TBM patients younger than 15 years old were enrolled. Out of 86 children, 36 (41.9%) received the regimen containing linezolid.
RESULTS: Thirty-two (88.9%) of 36 linezolid-treated cases had favorable outcomes, and 35 (70.0%) cases were successfully treated in the control group. The frequency of favorable outcome of linezolid group was significantly higher than that of control group (P = 0.037). In addition, compared with cases with fever clearance time of <1 week, the control group had more cases with fever clearance time of 1-4 weeks (P = 0.010) and >4 weeks (P = 0.000) than linezolid group. Furthermore, there was no significant difference in the frequency of adverse events between the two regimens (P = 0.896). In addition, the patients with adverse events were more likely to have treatment failure, the P value of which was 0.008.
CONCLUSIONS: Our data demonstrate that linezolid improves early outcome of childhood TBM. The low frequency of linezolid-associated adverse effects highlights the promising prospects of its use for treatment of childhood TBM.

PMID: 26901441 [PubMed - indexed for MEDLINE]

Notice NOT-AT-17-008 from the NIH Guide for Grants and Contracts

Notice NOT-AT-17-007 from the NIH Guide for Grants and Contracts

Notice NOT-AI-17-011 from the NIH Guide for Grants and Contracts