Imperial College London

Dr Nicky Whiffin

Faculty of MedicineNational Heart & Lung Institute

Research Fellow
 
 
 
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n.whiffin

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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49 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

Ingles J, Goldstein J, Thaxton C, Caleshu C, Corty EW, Crowley SB, Dougherty K, Harrison SM, McGlaughon J, Milko L, Morales A, Seifert BA, Strande N, Thomson K, van Tintelen JP, Wallace K, Walsh R, Wells Q, Whiff N, Witkowski L, Semsarian C, Ware JS, Hershberger RE, Funke Bet al., 2019, Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes, CIRCULATION-GENOMIC AND PRECISION MEDICINE, Vol: 12, ISSN: 2574-8300

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

Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R, Rahneva T, Wage R, Smith G, Venneri L, Tayal U, Auger D, Midwinter W, Whiffin N, Rajani R, Dungu JN, Pantazis A, Cook SA, Ware JS, Baksi AJ, Pennell DJ, Rosen SD, Cowie MR, Cleland JGF, Prasad SKet al., 2019, Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial, LANCET, Vol: 393, Pages: 61-73, ISSN: 0140-6736

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

Halliday BP, Wassail R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R, Tayal T, Wage R, Smith G, Venneri L, Tayal U, Auger D, Midwinter W, Whiffin N, Rajani R, Dungu JN, Pantazis A, Cook SA, Ware JS, Baksi AJ, Pennell DJ, Rosen SD, Cowie MR, Cleland JGF, Prasad SKet al., 2019, Brief Comment Video to the Recommended Article of the Month, REVISTA PORTUGUESA DE CARDIOLOGIA, Vol: 38, Pages: 71-71, ISSN: 0870-2551

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

Oates EC, Jones KJ, Donkervoort S, Charlton A, Brammah S, Smith JE, Ware JS, Yau KS, Swanson LC, Whiffin N, Peduto AJ, Bournazos A, Waddell LB, Farrar MA, Sampaio HA, Teoh HL, Lamont PJ, Mowat D, Fitzsimons RB, Corbett AJ, Ryan MM, O'Grady GL, Sandaradura SA, Ghaoui R, Joshi H, Marshall JL, Nolan MA, Kaur S, Punetha J, Toepf A, Harris E, Bakshi M, Genetti CA, Marttila M, Werlauff U, Streichenberger N, Pestronk A, Mazanti I, Pinner JR, Vuillerot C, Grosmann C, Camacho A, Mohassel P, Leach ME, Foley AR, Bharucha-Goebel D, Collins J, Connolly AM, Gilbreath HR, Iannaccone ST, Castro D, Cummings BB, Webster RI, Lazaro L, Vissing J, Coppens S, Deconinck N, Luk H-M, Thomas NH, Foulds NC, Illingworth MA, Ellard S, McLean CA, Phadke R, Ravenscroft G, Witting N, Hackman P, Richard I, Cooper ST, Kamsteeg E-J, Hoffman EP, Bushby K, Straub V, Udd B, Ferreiro A, North KN, Clarke NF, Lek M, Beggs AH, Boennemann CG, MacArthur DG, Granzier H, Davis MR, Laing NGet al., 2018, Congenital Titinopathy: Comprehensive characterization and pathogenic insights, ANNALS OF NEUROLOGY, Vol: 83, Pages: 1105-1124, ISSN: 0364-5134

JOURNAL ARTICLE

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

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, Jongbloed JDH, Macaya D, Manrai A, Orland K, Richard G, Spoonamore K, Thomas M, Thomson K, Vincent LM, Walsh R, Watkins H, Whiffin N, Ingles J, van Tintelen JP, Semsarian C, Ware JS, Hershberger R, Funke Bet al., 2018, Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel, GENETICS IN MEDICINE, Vol: 20, Pages: 351-359, ISSN: 1098-3600

JOURNAL ARTICLE

Biffi C, de Marvao A, Attard MI, Dawes TJW, Whiffin N, Bai W, Shi W, Francis C, Meyer H, Buchan R, Cook SA, Rueckert D, O'Regan DPet al., 2018, Three-dimensional cardiovascular imaging-genetics: a mass univariate framework, BIOINFORMATICS, Vol: 34, Pages: 97-103, ISSN: 1367-4803

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, Pages: E96-E96, ISSN: 0009-7330

CONFERENCE PAPER

Ingles J, Goldstein J, Caleshu C, Corty E, Crowley S, Dougherty K, McGlaughon J, Milko L, Morales A, Seifert B, Semsarian C, Strande N, Thaxton C, Thomson K, van Tintelen P, Wallace K, Walsh R, Ware J, Wells Q, Whiffin N, Wikowski L, Hershberger R, Funke Bet al., 2017, Evaluating Hypertrophic Cardiomyopathy Disease-Gene Associations Using the Clinical Genome Resource (ClinGen) Gene Curation Framework, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

CONFERENCE PAPER

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

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, Buchan R, Whiffin N, Newsome S, Walsh R, Barton P, Ware J, Cook S, Prasad Set al., 2017, EVALUATION OF TITIN CARDIOMYOPATHY IN PATIENTS WITH DILATED CARDIOMYOPATHY REVEALS A BLUNTED HYPERTROPHIC RESPONSE, AN EARLY ARRHYTHMIC RISK AND A SIGNIFICANT INTERACTION WITH ALCOHOL, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A95-A95, ISSN: 1355-6037

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

Tayal U, Newsome S, Voges I, Whiffin N, Buchan R, Halliday B, Lota A, Izgi C, Barton PJ, Baruah R, Jarman J, Frenneaux M, Pennell DJ, Ware JS, Cook SA, Prasad SKet al., 2017, MULTIMODALITY ASSESSMENT OF RISK IN DILATED CARDIOMYOPATHY-THE IMPORTANCE OF CMR, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A4-A4, ISSN: 1355-6037

CONFERENCE PAPER

Tayal U, Newsome S, Whiffin N, Buchan R, Walsh R, Barton PJ, Ware JS, Cook SA, Prasad SKet al., 2017, PRECISE PHENOTYPING WITH CMR IDENTIFIES MODERATE ALCOHOL CONSUMPTION AS AN IMPORTANT PHENOTYPIC MODIFIER OF TITIN CARDIOMYOPATHY, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 1355-6037

CONFERENCE PAPER

Tayal U, Buchan R, Whiffin N, Newsome S, Walsh R, Barton P, Ware J, Prasad S, Cook Set al., 2017, INTEGRATED ANALYSIS OF THE CLINICAL MANIFESTATIONS AND PHENOTYPIC DRIVERS OF TITIN CARDIOMYOPATHY, 66th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 2563-2563, ISSN: 0735-1097

CONFERENCE PAPER

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

Tayal U, Newsome S, Buchan R, Whiffin N, Walsh R, Ware J, Prasad SK, Cook SAet al., 2016, Defining titin cardiomyopathy: genotype- phenotype correlations in a large prospective cohort of dilated cardiomyopathy patients, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 365-365, ISSN: 0195-668X

CONFERENCE PAPER

Tayal U, Newsome S, Buchan R, Whiffin N, Walsh R, Ware J, Cook SA, Prasad SKet al., 2016, Genetic determinants of arrhythmia in dilated cardiomyopathy, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 206-206, ISSN: 0195-668X

CONFERENCE PAPER

Tayal U, Buchan RJ, Whiffin N, Newsome S, Mazzarotto F, Walsh R, Ware JS, Cook S, Prasad Set al., 2016, CLINICAL AND GENETIC CHARACTERISTICS OF FAMILIAL DILATED CARDIOMYOPATHY IN A LARGE UK PROSPECTIVE COHORT, Annual Conference of the British-Cardiovascular-Society (BCS) on Prediction and Prevention, Publisher: BMJ PUBLISHING GROUP, Pages: A103-A103, ISSN: 1355-6037

CONFERENCE PAPER

Tayal U, Buchan RJ, Whiffin N, Newsome S, Mazzarotto F, Walsh R, Ware JS, Prasad S, Cook Set al., 2016, EFFECTS OF TRUNCATING VARIANTS IN TITIN ON CARDIAC PHENOTYPE AND LEFT VENTRICULAR REMODELLING IN DILATED CARDIOMYOPATHY, Annual Conference of the British-Cardiovascular-Society (BCS) on Prediction and Prevention, Publisher: BMJ PUBLISHING GROUP, Pages: A102-A103, ISSN: 1355-6037

CONFERENCE PAPER

Tayal U, Newsome S, Buchan R, Whiffin N, Shakespeare C, Ware J, Cook SA, Prasad SKet al., 2016, The presence of a truncating mutation in titin independently associates with arrhythmic burden in patients with dilated cardiomyopathy, Publisher: WILEY-BLACKWELL, Pages: 156-156, ISSN: 1388-9842

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

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