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  • JOURNAL ARTICLE
    Walsh R, 2017,

    Defining the genetic architecture ofhypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes

    , European Heart Journal, ISSN: 1522-9645

    AimHypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM.Methods and resultsWe sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence.ConclusionWe show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.

  • JOURNAL ARTICLE
    Walsh R, Buchan R, Wilk A, John S, Felkin LE, Thomson KL, Chiaw TH, Loong CC, 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.

    , Eur Heart J

    AIM: Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. METHODS AND RESULTS: We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence. CONCLUSION: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.

  • JOURNAL ARTICLE
    Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, MacArthur DG, Farrall M, Cook SA, Watkins Het al., 2017,

    Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

    , GENETICS IN MEDICINE, Vol: 19, Pages: 192-203, ISSN: 1098-3600
  • JOURNAL ARTICLE
    Dawes TJW, Corden B, Cotter S, de Marvao A, Walsh R, Ware JS, Cook SA, O'Regan DPet al., 2016,

    Moderate Physical Activity in Healthy Adults Is Associated With Cardiac Remodeling

    , CIRCULATION-CARDIOVASCULAR IMAGING, Vol: 9, ISSN: 1941-9651
  • 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
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hollman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozeo L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won H-H, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, NcCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DGet al., 2016,

    Analysis of protein-coding genetic variation in 60,706 humans

    , NATURE, Vol: 536, Pages: 285-+, ISSN: 0028-0836
  • JOURNAL ARTICLE
    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
    Schafer S, de Marvao A, Adami E, Fiedler LR, Ng B, Khin E, Rackham O, 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, O'Regan D, Ware JS, Hubner N, Cook SAet al., 2016,

    Titin truncating variants affect heart function in disease cohorts and the general population

    , Nature Genetics, Vol: 49, Pages: 46-53, ISSN: 1546-1718

    Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.

  • JOURNAL ARTICLE
    Wang M, Sips P, Khin E, Rotival M, Sun X, Ahmed R, Widjaja AA, Schafer S, Yusoff P, Choksi PK, Ko NSJ, Singh MK, Epstein D, Guan Y, Houstek J, Mracek T, Nuskova H, Mikell B, Tan J, Pesce F, Kolar F, Bottolo L, Mancini M, Hubner N, Pravenec M, Petretto E, MacRae C, Cook SAet al., 2016,

    Wars2 is a determinant of angiogenesis

    , NATURE COMMUNICATIONS, Vol: 7, ISSN: 2041-1723
  • JOURNAL ARTICLE
    Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, Ramani G, Safirstein J, Boehmer J, Pauly DF, Wittstein IS, Thohan V, Zucker MJ, Liu P, Gorcsan J, McNamara DM, Seidman CE, Seidman JG, Arany Zet al., 2016,

    Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

    , NEW ENGLAND JOURNAL OF MEDICINE, Vol: 374, Pages: 233-241, ISSN: 0028-4793
  • JOURNAL ARTICLE
    Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC, Swist S, Gorham J, Yang L, Schafer S, Sheng CC, Haghighi A, Homsy J, Hubner N, Church G, Cook SA, Linke WA, Chen CS, Seidman JG, Seidman CEet al., 2015,

    Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy

    , SCIENCE, Vol: 349, Pages: 982-986, ISSN: 0036-8075
  • JOURNAL ARTICLE
    Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, Jin SC, Deanfield J, Giardini A, Porter GA, Kim R, Bilguvar K, Lopez-Giraldez F, Tikhonova I, Mane S, Romano-Adesman A, Qi H, Vardarajan B, Ma L, Daly M, Roberts AE, Russell MW, Mital S, Newburger JW, Gaynor JW, Breitbart RE, Iossifov I, Ronemus M, Sanders SJ, Kaltman JR, Seidman JG, Brueckner M, Gelb BD, Goldmuntz E, Lifton RP, Seidman CE, Chung WKet al., 2015,

    De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

    , SCIENCE, Vol: 350, Pages: 1262-1266, ISSN: 0036-8075
  • JOURNAL ARTICLE
    Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, L MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O'Regan DP, San TR, de Marvao A, W Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O'Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SAet al., 2015,

    Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

    , Sci Transl Med, Vol: 7

    The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.

  • JOURNAL ARTICLE
    Ruklisa D, Ware JS, Walsh R, Balding DJ, Cook SAet al., 2015,

    Bayesian models for syndrome- and gene-specific probabilities of novel variant pathogenicity

    , GENOME MEDICINE, Vol: 7, ISSN: 1756-994X
  • JOURNAL ARTICLE
    Maatz H, Jens M, Liss M, Schafer S, Heinig M, Kirchner M, Adami E, Rintisch C, Dauksaite V, Radke MH, Selbach M, Barton PJ, Cook SA, Rajewsky N, Gotthardt M, Landthaler M, Hubner Net al., 2014,

    RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing.

    , J Clin Invest, Vol: 124, Pages: 3419-3430

    Mutations in the gene encoding the RNA-binding protein RBM20 have been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure, presumably through altering cardiac RNA splicing. Here, we combined transcriptome-wide crosslinking immunoprecipitation (CLIP-seq), RNA-seq, and quantitative proteomics in cell culture and rat and human hearts to examine how RBM20 regulates alternative splicing in the heart. Our analyses revealed the presence of a distinct RBM20 RNA-recognition element that is predominantly found within intronic binding sites and linked to repression of exon splicing with RBM20 binding near 3' and 5' splice sites. Proteomic analysis determined that RBM20 interacts with both U1 and U2 small nuclear ribonucleic particles (snRNPs) and suggested that RBM20-dependent splicing repression occurs through spliceosome stalling at complex A. Direct RBM20 targets included several genes previously shown to be involved in DCM as well as genes not typically associated with this disease. In failing human hearts, reduced expression of RBM20 affected alternative splicing of several direct targets, indicating that differences in RBM20 expression may affect cardiac function. Together, these findings identify RBM20-regulated targets and provide insight into the pathogenesis of human heart failure.

  • JOURNAL ARTICLE
    Herman DS, Lam L, Taylor MRG, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJR, Cook SA, Mestroni L, Seidman JG, Seidman CEet al., 2012,

    Truncations of Titin Causing Dilated Cardiomyopathy

    , NEW ENGLAND JOURNAL OF MEDICINE, Vol: 366, Pages: 619-628, ISSN: 0028-4793
  • JOURNAL ARTICLE
    McDermott-Roe C, Ye J, Ahmed R, Sun X-M, Serafin A, Ware J, Bottolo L, Muckett P, Canas X, Zhang J, Rowe GC, Buchan R, Lu H, Braithwaite A, Mancini M, Hauton D, Marti R, Garcia-Arumi E, Hubner N, Jacob H, Serikawa T, Zidek V, Papousek F, Kolar F, Cardona M, Ruiz-Meana M, Garcia-Dorado D, Comella JX, Felkin LE, Barton PJR, Arany Z, Pravenec M, Petretto E, Sanchis D, Cook SAet al., 2011,

    Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

    , NATURE, Vol: 478, Pages: 114-118, ISSN: 0028-0836

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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