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Circ Cardiovasc Genet. 2013 Apr;6(2):144-53. doi: 10.1161/CIRCGENETICS.111.000062. Epub 2013 Feb 15.

Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy.

Collaborators (402)

Gabriel SB, Altshuler DM, Abecasis GR, Allayee H, Cresci S, Daly MJ, de Bakker PI, DePristo MA, Do R, Donnelly P, Farlow DN, Fennell T, Garimella K, Hazen SL, Hu Y, Jordan DM, Jun G, Kathiresan S, Kang HM, Kiezun A, Lettre G, Li B, Li M, Newton-Cheh CH, Padmanabhan S, Peloso G, Pulit S, Rader DJ, Reich D, P M, Rivas MA, Schwartz S, Scott L, Siscovick DS, Spertus JA, Stitziel NO, Stoletzki N, Sunyaev SR, Voight BF, Willer CJ, Rich SS, Akylbekova E, Atwood LD, Ballantyne CM, Barbalic M, Barr R, Benjamin EJ, Bis J, Boerwinkle E, Bowden W, Brody J, Budoff M, Burke G, Buxbaum S, Carr J, Chen DT, Chen IY, Chen WM, Concannon P, Crosby J, Cupples L, D'Agostino R, DeStefano AL, Dreisbach A, Dupuis J, Durda J, Ellis J, Folsom AR, Fornage M, Fox CS, Fox E, Funari V, K S, Gardin J, Goff D, Gordon O, Grody W, Gross M, Guo X, Hall IM, Heard-Costa NL, Heckbert R, Heintz N, Herrington DM, Hickson D, Huang J, Hwang SJ, Jacobs DR, Jenny NS, Johnson AD, Johnson CW, Kawut S, Kronmal R, Kurz R, Lange EM, Lange LA, Larson MG, Lawson M, Lewis CE, Levy D, Li D, Lin H, Liu C, Liu J, Liu K, Liu X, Liu Y, Longstreth WT, Loria C, Lumley T, Lunetta K, Mackey AJ, Mackey R, Manichaikul A, Maxwell T, McKnight B, Meigs JB, Morrison AC, Musani SK, Mychaleckyj JC, Nettleton JA, North K, O'Donnell CJ, O'Leary D, Ong F, Palmas W, Pankow JS, Pankratz ND, Paul S, Perez M, Person SD, Polak J, Post WS, Psaty BM, Quinlan AR, Raffel LJ, S V, Reiner AP, Hutchinson F, Rice K, Rotter JI, Sanders JP, Schreiner P, Seshadri S, Shea S, Sidney S, Silverstein K, S D, Smith NL, Sotoodehnia N, Srinivasan A, Taylor HA, Taylor K, Thomas F, Tracy RP, Tsai MY, Volcik KA, Wassel CL, Watson K, Wei G, White W, Wiggins KL, Wilk JB, Williams O, Wilson G, Wilson JG, Wolf P, Zakai NA, Hardy J, Meschia JF, Nalls M, Rich SS, Singleton A, Worrall B, Bamshad MJ, Barnes KC, Abdulhamid I, Accurso F, Anbar R, Beaty T, Bigham A, Black P, Bleecker E, Buckingham K, Cairns AM, Chen WM, Caplan D, Chatfield B, Chidekel A, Cho M, Christiani DC, Crapo JD, Crouch J, Daley D, Dang A, Dang H, De Paula A, DeCelie-Germana J, Dozor A, Drumm M, Dyson M, Emerson J, Emond MJ, Ferkol T, Fink R, Foster C, Froh D, Gao L, Gershan W, Gibson RL, Godwin E, Gondor M, Gutierrez H, Hansel NN, Hassoun PM, Hiatt P, Hokanson JE, Howenstine M, K L, Kanga J, Kim Y, Knowles MR, Konstan M, Lahiri T, Laird N, Lange C, Lin L, Lin X, Louie TL, Lynch D, Make B, Martin TR, Mathai SC, Mathias RA, McNamara J, McNamara S, Meyers D, Millard S, Mogayzel P, Moss R, Murray T, Nielson D, Noyes B, O'Neal W, Orenstein D, O'Sullivan B, Pace R, Pare P, Parker H, Passero MA, Perkett E, Prestridge A, Rafaels NM, Ramsey B, Regan E, Ren C, Retsch-Bogart G, Rock M, Rosen A, Rosenfeld M, Ruczinski I, Sanford A, Schaeffer D, Sell C, Sheehan D, Silverman EK, Sin D, Spencer T, Stonebraker J, Tabor HK, Varlotta L, Vergara CI, Weiss R, Wigley F, Wise RA, Wright FA, Wurfel MM, Zanni R, Zou F, Nickerson DA, Rieder MJ, Green P, Shendure J, Akey JM, Bamshad MJ, Bustamante CD, Crosslin DR, Eichler EE, Fox P, Fu W, Gordon A, Gravel S, Jarvik GP, Johnsen JM, Kan M, Kenny EE, M J, Lara-Garduno F, Leal SM, Liu DJ, McGee S, D T, Paeper B, Robertson PD, Smith D, Staples JC, Tennessen JA, Turner EH, Wang G, Yi Q, Jackson R, North K, Peters U, Hutchinson F, Carlson CS, Hutchinson F, Anderson G, Anton-Culver H, Assimes TL, Auer PL, Beresford S, Bizon C, Black H, Brunner R, Brzyski R, Burwen D, Caan B, Carty CL, Chlebowski R, Cummings S, Curb J, Eaton CB, Ford L, Franceschini N, Fullerton SM, Gass M, Geller N, Heiss G, V B, Hsu L, Hutchinson F, Hutter CM, Hutchinson F, Ioannidis J, Jiao S, Johnson KC, Kooperberg C, Hutchinson F, Kuller L, LaCroix A, Lakshminarayan K, Lane D, Lange EM, A L, Lasser N, LeBlanc E, Lewis CE, Li KP, Limacher M, Lin DY, Logsdon BA, Ludlam S, Manson JE, Margolis K, Martin L, Washington G, McGowan J, Monda KL, Kotchen JM, Nathan L, Ockene J, O'Sullivan MJ, Phillips LS, Prentice RL, Hutchinson F, Reiner AP, Robbins J, Robinson JG, E J, Sangi-Haghpeykar H, Sarto GE, Shumaker S, Simon MS, Stefanick ML, Stein E, Tang H, Taylor KC, A C, Thornton TA, Van Horn L, Vitolins M, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Zeng D, Applebaum-Bowden D, Feolo M, Gan W, Paltoo DN, Rossouw JE, Sholinsky P, Sturcke A.

Abstract

BACKGROUND- Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. METHODS AND RESULTS- We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. CONCLUSIONS- These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

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