Imperial College London

DrPaulBarton

Faculty of MedicineNational Heart & Lung Institute

Honorary Senior Research Fellow
 
 
 
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Contact

 

+44 (0)20 7351 8140p.barton Website

 
 
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Location

 

2054Sydney StreetRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

188 results found

Garcia-Pavia P, Kim Y, Alejandra Restrepo-Cordoba M, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, Ito K, Willcox JA, Arany Z, Li J, Owens AT, Govind R, Nuñez B, Mazaika E, Bayes-Genis A, Walsh R, Finkelman B, Lupon J, Whiffin N, Serrano I, Midwinter W, Wilk A, Bardaji A, Ingold N, Buchan R, Tayal U, Pascual-Figal DA, de Marvao A, Ahmad M, Garcia-Pinilla JM, Pantazis A, Dominguez F, Baksi AJ, O'Regan DP, Rosen SD, Prasad SK, Lara-Pezzi E, Provencio M, Lyon AR, Alonso-Pulpon L, Cook SA, DePalma SR, Barton PJR, Aplenc R, Seidman JG, Ky B, Ware JS, Seidman CEet al., 2019, Genetic Variants Associated with Cancer Therapy-Induced Cardiomyopathy., Circulation

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders. These parameters incompletely account for substantial inter-individual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 CCM patients from three cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped breast cancer adults (n=73) and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including nine pre-specified genes were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas (TCGA) participants (n=2053), healthy volunteers (n=445), and ancestry-matched reference population. Clinical characteristics and outcomes were assessed, stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4-9 years after chemotherapy; 90% of these patients received anthracyclines. Adult CCM patients had cardiovascular risk factors similar to the U.S. POPULATION: Among nine prioritized genes CCM patients had more rare protein-altering variants than comparative cohorts (p≤1.98e-04). Titin-truncating variants (TTNtv) predominated, occurring in 7.5% CCM patients versus 1.1% TCGA participants (p=7.36e-08), 0.7% healthy volunteers (p=3.42e-06), and 0.6% reference population (p=5.87e-14). Adult CCM patients with TTNtv experienced more heart failure and atrial fibrillation (p=0.003) and impaired myocardial recovery (p=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wildtype (p=0.0004 and p<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtv, increased the risk for CCM in children and adults, and advers

JOURNAL ARTICLE

Walsh R, Mazzarotto F, Whiffin N, Buchan R, Midwinter W, Wilk A, Li N, Felkin L, Ingold N, Govind R, Ahmad M, Mazaika E, Allouba M, Zhang X, de Marvao A, Day SM, Ashley E, Colan SD, Michels M, Pereira AC, Jacoby D, Ho CY, Thomson KL, Watkins H, Barton PJR, Olivotto I, Cook SA, Ware JSet al., 2019, Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy, GENOME MEDICINE, Vol: 11, ISSN: 1756-994X

JOURNAL ARTICLE

Whiffin N, Roberts AM, Minikel E, Zappala Z, Walsh R, O'Donnell-Luria AH, Karczewski KJ, Harrison SM, Thomson KL, Sage H, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur DG, Ware JSet al., 2019, Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 104, Pages: 187-190, ISSN: 0002-9297

JOURNAL ARTICLE

Horvat C, Johnson R, Lam L, Munro J, Mazzarotto F, Roberts AM, Herman DS, Parfenov M, Haghighi A, McDonough B, DePalma SR, Keogh AM, Macdonald PS, Hayward CS, Roberts A, Barton PJR, Felkin LE, Giannoulatou E, Cook SA, Seidman JG, Seidman CE, Fatkin Det al., 2019, A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy, GENETICS IN MEDICINE, Vol: 21, Pages: 133-143, ISSN: 1098-3600

JOURNAL ARTICLE

Dominguez F, Cuenca S, Bilinska Z, Toro R, Villard E, Barriales-Villa R, Pablo Ochoa J, Asselbergs F, Sammani A, Franaszczyk M, Akhtar M, Jose Coronado-Albi M, Rangel-Sousa D, Rodriguez-Palomares JF, Jimenez-Jaimez J, Manuel Garcia-Pinilla J, Ripoll-Vera T, Victoria Mogollon-Jimenez M, Fontalba-Romero A, Garcia-Medina D, Palomino-Doza J, de Gonzalo-Calvo D, Cicerchia M, Salazar-Mendiguchia J, Salas C, Pankuweit S, Hey TM, Mogensen J, Barton PJ, Charron P, Elliott P, Garcia-Pavia Pet al., 2018, Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 72, Pages: 2471-2481, ISSN: 0735-1097

JOURNAL ARTICLE

Whiffin N, Walsh R, Govind R, Edwards M, Ahmad M, Zhang X, Tayal U, Buchan R, Midwinter W, Wilk AE, Najgebauer H, Francis C, Wilkinson S, Monk T, Brett L, O'Regan DP, Prasad SK, Morris-Rosendahl DJ, Barton PJR, Edwards E, Ware JS, Cook SAet al., 2018, CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation, GENETICS IN MEDICINE, Vol: 20, Pages: 1246-1254, ISSN: 1098-3600

JOURNAL ARTICLE

Restrepo Cordoba MA, Barton PJ, Bayes-Genis A, Govind R, Serrano I, Midwinter W, Pascual-Figal D, Wilk A, Pinilla JMG, Cook SA, Provencio M, Lyon A, Alonso-Pulpon L, Ware JS, Garcia-Pavia Pet al., 2018, Genetic predisposing factors in chemotherapy-induced cardiomyopathy, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 282-283, ISSN: 0195-668X

CONFERENCE PAPER

Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar-Mendiguchia J, Manuel Garcia-Pinilla J, Pascual-Figal DA, Nunez J, Guzzo-Merello G, Gonzalez-Vioque E, Bardaji A, Manito N, Lopez-Garrido MA, Padron-Barthe L, Edwards E, Whiffin N, Walsh R, Buchan RJ, Midwinter W, Wilk A, Prasad S, Pantazis A, Baski J, O'Regan DP, Alonso-Pulpon L, Cook SA, Lara-Pezzi E, Barton PJ, Garcia-Pavia Pet al., 2018, Genetic Etiology for Alcohol-Induced Cardiac Toxicity, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 71, Pages: 2293-2302, ISSN: 0735-1097

JOURNAL ARTICLE

de Marvao A, Biffi C, Walsh R, Doumou G, Dawes T, Shi W, Bai W, Berry A, Buchan R, Pierce I, Tokarczuk P, Statton B, Francis C, Duan J, Quinlan M, Felkin L, Le T-T, Bhuva A, Tang HC, Barton P, Chin CW-L, Rueckert D, Ware J, Prasad S, O'Regan DP, Cook SAet al., 2018, DEFINING THE EFFECTS OF GENETIC VARIATION USING MACHINE LEARNING ANALYSIS OF CMRS: A STUDY IN HYPERTROPHIC CARDIOMYOPATHY AND IN A HEALTHY POPULATION, Joint Meeting of the British-Society-of-Cardiovascular-Imaging/British-Society-of-Cardiovascular-CT, British-Society-of-Cardiovascular-Magnetic-Resonance and British-Nuclear-Cardiac-Society on British Cardiovascular Imaging, Publisher: BMJ PUBLISHING GROUP, Pages: A7-A8, ISSN: 1355-6037

CONFERENCE PAPER

Walsh R, Buchan R, Wilk A, John S, Felkin LE, Thomson KL, Chiaw TH, Loong CCW, Pua CJ, Raphael C, Prasad S, Barton PJ, Funke B, Watkins H, Ware JS, Cook SAet al., 2017, Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes, EUROPEAN HEART JOURNAL, Vol: 38, Pages: 3461-3468, ISSN: 0195-668X

JOURNAL ARTICLE

Corden B, Jarman J, Whiffin N, Tayal U, Buchan R, Sehmi J, Harper A, Midwinter W, Lascelles K, Markides V, Mason M, Pennell DJ, Barton PJ, Prasad SK, Wong T, Cook SA, Ware JSet al., 2017, Titin Truncating Variants Predict Life-threatening Arrhythmias in Patients With Dilated Cardiomyopathy, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

CONFERENCE PAPER

Tayal U, Newsome S, Buchan R, Whiffin N, Halliday B, Lota A, Roberts A, Baksi AJ, Voges I, Midwinter W, Wilk A, Govind R, Walsh R, Daubeney P, Jarman JWE, Baruah R, Frenneaux M, Barton PJ, Pennell D, Ware JS, Prasad SK, Cook SAet al., 2017, Phenotype and Clinical Outcomes of Titin Cardiomyopathy, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 70, Pages: 2264-2274, ISSN: 0735-1097

JOURNAL ARTICLE

Whiffin N, Minikel E, Walsh R, O'Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur D, Ware JSet al., 2017, Using high-resolution variant frequencies to empower clinical genome interpretation, GENETICS IN MEDICINE, Vol: 19, Pages: 1151-1158, ISSN: 1098-3600

JOURNAL ARTICLE

Heinig M, Adriaens ME, Schafer S, van Deutekom HWM, Lodder EM, Ware JS, Schneider V, Felkin LE, Creemers EE, Meder B, Katus HA, Ruehle F, Stoll M, Cambien F, Villard E, Charron P, Varro A, Bishopric NH, George AL, dos Remedios C, Moreno-Moral A, Pesce F, Bauerfeind A, Rueschendorf F, Rintisch C, Petretto E, Barton PJ, Cook SA, Pinto YM, Bezzina CR, Hubner Net al., 2017, Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy, GENOME BIOLOGY, Vol: 18, ISSN: 1474-760X

JOURNAL ARTICLE

Whiffin N, Walsh R, Govind R, Edwards M, Ahmad M, Zhang X, Tayal U, Buchan R, Midwinter W, Wilk A, Najgebauer H, Francis C, Wilkinson S, Monk T, Brett L, O'Regan D, Prasad S, Morris-Rosendahl D, Barton P, Edwards E, Ware J, Cook Set al., 2017, CardioClassifier: demonstrating the power of disease- and gene-specific computational decision support for clinical genome interpretation

Purpose: Internationally-adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier (www.cardioclassifier.org), a semi-automated decision-support tool for inherited cardiac conditions (ICCs). Methods: CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules. Results: We benchmarked CardioClassifier on 57 expertly-curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically-actionable variants (64/219 vs 156/219, Fishers P=1.1x10-18), with important false positives; illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually-curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. Conclusion: CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible and interactive variant pathogenicity reports, according to best practice guidelines.

WORKING PAPER

Tayal U, Newsome S, Walsh R, Voges I, Whiffin N, Buchan R, Halliday B, Lota A, Barton PJ, Baruah R, Jarman J, Frenneaux M, Ware JS, Cook SA, Prasad SKet al., 2017, Defining the genetic architecture of dilated cardiomyopathy- insights from population genetic variation and the role of titin, Publisher: OXFORD UNIV PRESS, Pages: 821-822, ISSN: 0195-668X

CONFERENCE PAPER

Tayal U, Newsome S, Buchan R, Whiffin N, Walsh R, Barton PJ, Ware JS, Cook SA, Prasad SKet al., 2017, Truncating Variants in Titin Independently Predict Early Arrhythmias in Patients With Dilated Cardiomyopathy, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 69, Pages: 2466-2468, ISSN: 0735-1097

JOURNAL ARTICLE

Rea G, Homfray T, Till J, Roses-Noguer F, Buchan RJ, Wilkinson S, Wilk A, Walsh R, John S, Mckee S, Stewart FJ, Murday V, Taylor RW, Ashworth M, Baksi AJ, Daubeney P, Prasad S, Barton PJR, Cook SA, Ware JSet al., 2017, Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11, COLD SPRING HARBOR MOLECULAR CASE STUDIES, Vol: 3, ISSN: 2373-2873

JOURNAL ARTICLE

Schafer S, de Marvao A, Adami E, Fiedler LR, Ng B, Khin E, Rackham OJL, van Heesch S, Pua CJ, Kui M, Walsh R, Tayal U, Prasad SK, Dawes TJW, Ko NSJ, Sim D, Chan LLH, Chin CWL, Mazzarotto F, Barton PJ, Kreuchwig F, de Kleijn DPV, Totman T, Biffi C, Tee N, Rueckert D, Schneider V, Faber A, Regitz-Zagrosek V, Seidman JG, Seidman CE, Linke WA, Kovalik J-P, O'Regan D, Ware JS, Hubner N, Cook SAet al., 2017, Titin-truncating variants affect heart function in disease cohorts and the general population, NATURE GENETICS, Vol: 49, Pages: 46-53, ISSN: 1061-4036

JOURNAL ARTICLE

Gomez-Salinero JM, Lopez-Olaneta MM, Ortiz-Sanchez P, Larrasa-Alonso J, Gatto A, Felkin LE, Barton PJR, Navarro-Lerida I, del Pozo MA, Garcia-Pavia P, Sundararaman B, Giovinazo G, Yeo GW, Lara-Pezzi Eet al., 2016, The Calcineurin Variant CnA beta 1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation, CELL CHEMICAL BIOLOGY, Vol: 23, Pages: 1372-1382, ISSN: 2451-9448

JOURNAL ARTICLE

Whiffin N, Minikel E, Walsh R, O'Donnell-Luria A, Karczewski K, Ing A, Barton P, Funke B, Cook S, MacArthur D, Ware Jet al., 2016, Using high-resolution variant frequencies to empower clinical genome interpretation

Whole exome and genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognised as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants. Here we present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets. Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, and identifies 43 variants previously reported as pathogenic that can now be reclassified. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.

JOURNAL ARTICLE

Felkin LE, Walsh R, Ware JS, Yacoub MH, Birks EJ, Barton PJR, Cook SAet al., 2016, Recovery of Cardiac Function in Cardiomyopathy Caused by Titin Truncation, JAMA CARDIOLOGY, Vol: 1, Pages: 234-235, ISSN: 2380-6583

JOURNAL ARTICLE

Fatkin D, Lam L, Herman DS, Benson CC, Felkin LE, Barton PJR, Walsh R, Candan S, Ware JS, Roberts AM, Chung WK, Smoot L, Bornaun H, Keogh AM, Macdonald PS, Hayward CS, Seidman JG, Roberts AE, Cook SA, Seidman CEet al., 2016, Titin truncating mutations: A rare cause of dilated cardiomyopathy in the young, PROGRESS IN PEDIATRIC CARDIOLOGY, Vol: 40, Pages: 41-45, ISSN: 1058-9813

JOURNAL ARTICLE

Rea G, Ware JS, Homfray T, Till J, Roses-Noguer F, Buchan R, Wilkinson S, Wilk A, Walsh R, John S, McKee S, Stewart FJ, Murday V, Taylor RW, Baksi AJ, Daubeney P, Prasad S, Barton PJR, Cook SAet al., 2016, HISTIOCYTOID CARDIOMYOPATHY AND MICROPHTHALMIA WITH LINEAR SKIN DEFECTS SYNDROME: PHENOTYPES LINKED BY TRUNCATING VARIANTS IN NDUFB11, Annual Meeting of the British-Congenital-Cardiac-Association, Publisher: BMJ PUBLISHING GROUP, Pages: A18-A18, ISSN: 1355-6037

CONFERENCE PAPER

Pua CJ, Bhalshankar J, Miao K, Walsh R, John S, Lim SQ, Chow K, Buchan R, Soh BY, Lio PM, Lim J, Schafer S, Lim JQ, Tan P, Whiffin N, Barton PJ, Ware JS, Cook SAet al., 2016, Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 9, Pages: 3-11, ISSN: 1937-5387

JOURNAL ARTICLE

Barbato E, Barton PJ, Bartunek J, Huber S, Ibanez B, Judge DP, Lara-Pezzi E, Stolen CM, Taylor A, Hall JLet al., 2015, Review and Updates in Regenerative and Personalized Medicine, Preclinical Animal Models, and Clinical Care in Cardiovascular Medicine, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 8, Pages: 466-474, ISSN: 1937-5387

JOURNAL ARTICLE

Buyandelger B, Mansfield C, Kostin S, Choi O, Roberts AM, Ware JS, Mazzarotto F, Pesce F, Buchan R, Isaacson RL, Vouffo J, Gunkel S, Knoll G, McSweeney SJ, Wei H, Perrot A, Pfeiffer C, Toliat MR, Ilieva K, Krysztofinska E, Lopez-Olaneta MM, Gomez-Salinero JM, Schmidt A, Ng K-E, Teucher N, Chen J, Teichmann M, Eilers M, Haverkamp W, Regitz-Zagrosek V, Hasenfuss G, Braun T, Pennell DJ, Gould I, Barton PJR, Lara-Pezzi E, Schaefer S, Huebner N, Felkin LE, O'Regan DP, Brand T, Milting H, Nuernberg P, Schneider MD, Prasad S, Petretto E, Knoll Ret al., 2015, ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 8, Pages: 643-652, ISSN: 1942-325X

JOURNAL ARTICLE

Garnier S, Hengstenberg C, Lamblin N, Dubourg O, De Groote P, Fauchier L, Trochu J-N, Arbustini E, Esslinger U, Barton PJ, Meder B, Katus H, Frese K, Komajda M, Cook SA, Isnard R, Tiret L, Villard E, Charron Pet al., 2015, Involvement of BAG3 and HSPB7 loci in various etiologies of systolic heart failure: Results of a European collaboration assembling more than 2000 patients, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 189, Pages: 105-107, ISSN: 0167-5273

JOURNAL ARTICLE

Fletcher ME, Boshier PR, Wakabayashi K, Keun HC, Smolenski RT, Kirkham PA, Adcock IM, Barton PJ, Takata M, Marczin Net al., 2015, Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 308, Pages: L1274-L1285, ISSN: 1040-0605

JOURNAL ARTICLE

Rea G, Petyrka J, Vieira M, Buchan R, Wilkinson S, Walsh R, John S, Barton PJR, Ware JS, Prasad S, Cook SAet al., 2015, THE GENETIC SIGNATURE IN ISCHAEMIC HEART DISEASE WITH MYOCARDIAL INFARCTION (MI) AND SIGNIFICANT LEFT VENTRICULAR (LV) DYSFUNCTION, British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes, Publisher: BMJ PUBLISHING GROUP, Pages: A97-A97, ISSN: 1355-6037

CONFERENCE PAPER

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