Titin Variants in Dilated Cardiomyopathy

TTN Transcript / Exon Structure & Truncating Variants in Cardiomyopathy Studies


Titin Variant Study - STM 2015

Science Translational Medicine paper describing the distribution of TTNtv in DCM, healthy subjects and population controls. (2015)

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.
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, 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, 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 SA, .
Sci Transl Med. 2015 7(270):270ra6. doi: 10.1126/scitranslmed.3010134.

Patient cohorts analysed in this study

CohortDescriptionStatusSizeTTNtv %
DCM-PROProspective DCM patients from Royal Brompton HospitalDCM37414.4%
DCM-ES *End-stage non-ischemic DCM patients from Harefield HospitalDCM15524.5%
DCM-REPLReplication DCM cohort from St Vincent's Hospital and Victor Chang Cardiovascular InstituteDCM16319.0%
HEALTHY-ICClinically screened healthy controls recruited from Imperial College, LondonHEALTHY3082.6%
WHIReplication control cohort from The Women's Health Initiative (WHI)CONTROL6671.3%
FHSParticipants in the Framingham Heart Study (FHS) Offspring Cohort, European ancestryCONTROL16231.3%
JHSRandom participants in the Jackson Heart Study (JHS), African-American populationCONTROL19801.6%

* Please note 71 of these patients were also included in DCM-B cohort from the 2012 NEJM study.

Truncating variants identified in this study

CohortPatient IDExonBandVariant (CDS)Variant (protein)Variant Type
DCM-PRO10AP01669 near Z-diskc.4724_4728delTGAAAp.Met1575SerfsX6frameshift
DCM-PRO10RW00786 I-bandc.8307_8308delTGp.Ala2770HisfsX4frameshift
DCM-PRO12FB00047 c.13022C>Gp.Ser4341Xnonsense
DCM-PRO10DW00512 I-bandc.12643_12644delCAp.Gln4215ValfsX16frameshift
DCM-PRO14MW01583 I-bandc.12757C>Tp.Gln4253Xnonsense
DCM-PRO10GG01869 I-bandc.27607G>Ap.Glu9203Lysother splice site
DCM-PRO10JF01835 I-bandc.29042-2A>Cessential splice site
DCM-PRO12SK00375 I-bandc.29062delGp.Ala9688GlnfsX7frameshift
DCM-PRO12PB00376 I-bandc.31763-1G>Aessential splice site
DCM-PRO10SB00367 I-bandc.32888-1delGessential splice site
DCM-PRO12MD01102 I-bandc.33418+1G>Aessential splice site
DCM-PRO12MA01291 I-bandc.39044-9T>Aother splice site
DCM-PRO10RC00179 I-bandc.41447delGp.Gly13816AlafsX18frameshift
DCM-PRO10PC00581 I-bandc.41473C>Tp.Arg13825Xnonsense
DCM-PRO10JM01592 I-bandc.43792delGp.Val14598Xframeshift
DCM-PRO10BC00144 I-bandc.45756dupAp.Tyr15253IlefsX15frameshift
DCM-PRO10WS00448 I-bandc.45812T>Gp.Leu15271Xnonsense
DCM-PRO10VS00240 A-bandc.47697C>Ap.Cys15899Xnonsense
DCM-PRO10DR00069 A-bandc.47875+1G>Aessential splice site
DCM-PRO10CH00929 A-bandc.48527G>Ap.Trp16176Xnonsense
DCM-PRO10JN00724 A-bandc.50170C>Tp.Arg16724Xnonsense
DCM-PRO10LP00987 A-bandc.50170C>Tp.Arg16724Xnonsense
DCM-PRO10RN00513 A-bandc.50170C>Tp.Arg16724Xnonsense
DCM-PRO10LB00067 A-bandc.52035_52036insTTp.Leu17346PhefsX4frameshift
DCM-PRO10DH00882 A-bandc.52223_52227dupAGAAAp.Asp17410ArgfsX25frameshift
DCM-PRO12AM00400 A-bandc.53881+1G>Tessential splice site
DCM-PRO10JS00726 A-bandc.53881+5G>Aother splice site
DCM-PRO10HH00944 A-bandc.55303-1G>Aessential splice site
DCM-PRO10JF01881 A-bandc.55525_55531delGACAGGAp.Asp18509SerfsX29frameshift
DCM-PRO10SF00976 A-bandc.55525_55531delGACAGGAp.Asp18509SerfsX29frameshift
DCM-PRO10RN00513 A-bandc.57544+4A>Gother splice site
DCM-PRO10AL00811 A-bandc.58732+2T>Cessential splice site
DCM-PRO12SR01222 A-bandc.60931C>Tp.Arg20311Xnonsense
DCM-PRO10TM00933 A-bandc.63025C>Tp.Arg21009Xnonsense
DCM-PRO10CS01472 A-bandc.69630C>Ap.Tyr23210Xnonsense
DCM-PRO12JL01327 A-bandc.74306dupAp.Asn24769LysfsX2frameshift
DCM-PRO10BK01803 A-bandc.78184G>Tp.Glu26062Xnonsense
DCM-PRO10JC00262 A-bandc.78507delTp.Gly26170ValfsX3frameshift
DCM-PRO10DM00077 A-bandc.81262_81269delCAGATGCTp.Gln27088CysfsX5frameshift
DCM-PRO10PP00413 A-bandc.81262_81269delCAGATGCTp.Gln27088CysfsX5frameshift
DCM-PRO12NP00167 A-bandc.81321C>Gp.Tyr27107Xnonsense
DCM-PRO10CP00605 A-bandc.82513delAp.Ile27505PhefsX20frameshift
DCM-PRO10PP00465 A-bandc.85090C>Tp.Arg28364Xnonsense
DCM-PRO12MH00114 A-bandc.86640delCp.His28881ThrfsX2frameshift
DCM-PRO12JL00046 A-bandc.86967G>Ap.Trp28989Xnonsense
DCM-PRO12ML01299 A-bandc.87716delGp.Gly29239AspfsX32frameshift
DCM-PRO10MV00215 A-bandc.89750dupGp.Val29918SerfsX3frameshift
DCM-PRO10TD00812 A-bandc.90086_90088delAAGinsAp.Glu30029AspfsX7frameshift
DCM-PRO10KF00073 A-bandc.92683C>Tp.Arg30895Xnonsense
DCM-PRO10AG01687 A-bandc.94849_94855delGATGCCCp.Ala31618TyrfsX37frameshift
DCM-PRO10KW01906 A-bandc.95415_95416+2delCAGTessential splice site
DCM-PRO10CS01784 A-bandc.98265_98268dupAACAp.His32757AsnfsX4frameshift
DCM-PRO14CT01557 M-bandc.101996G>Ap.Trp33999Xnonsense
DCM-PRO12PF00041 M-bandc.106629delAp.Ala35544ProfsX2frameshift
DCM-ES20HS01530 near Z-diskc.3100G>Ap.Val1034Metother splice site
DCM-ES20SF01658 near Z-diskc.3100G>Ap.Val1034Metother splice site
DCM-ES20AH01746 near Z-diskc.3100G>Ap.Val1034Metother splice site
DCM-ES20JL01558 c.14470_14471insCACACTCCATAp.R4824fsframeshift
DCM-ES20VW01643 I-bandc.40558G>Cp.Val13520Leuother splice site
DCM-ES20JT01288 I-bandc.44281C>Tp.Pro14761Serother splice site
DCM-ES20MC01968 I-bandc.44281+1G>Aessential splice site
DCM-ES20SG01639 I-bandc.46236C>Ap.C15412*nonsense
DCM-ES20JH01781 I-bandc.46782C>Ap.Tyr15594*nonsense
DCM-ES20JB01501 A-bandc.49346-1G>Aessential splice site
DCM-ES20RD01430 A-bandc.50247_50247delTp.F16749fsframeshift
DCM-ES20JL01448 A-bandc.53488G>Tp.G17830*nonsense
DCM-ES20PD01505 A-bandc.58172delAp.Asp19391fsframeshift
DCM-ES20VW01643 A-bandc.59627-1G>Aessential splice site
DCM-ES20EG01127 A-bandc.63601C>Tp.Arg21201*nonsense
DCM-ES20SW01468 A-bandc.64453C>Tp.R21485*nonsense
DCM-ES20JD01577 A-bandc.67495C>Tp.R22499*nonsense
DCM-ES20PS01433 A-bandc.69412+1G>Aessential splice site
DCM-ES20CW01447 A-bandc.69843_69843delAp.K23281fsframeshift
DCM-ES20HS01530 A-bandc.70791_70791delAp.E23597fsframeshift
DCM-ES20FG01148 A-bandc.74338C>Tp.Arg24780*nonsense
DCM-ES20SF01123 A-bandc.76116_76117insAp.Asn25372fsframeshift
DCM-ES20SB01532 A-bandc.76383_76386delTAATp.Asn25462fsframeshift
DCM-ES20DH01701 A-bandc.81518delCp.Pro27173fsframeshift
DCM-ES20LN01500 A-bandc.86459_86460delCTp.S28820fsframeshift
DCM-ES20BM01499 A-bandc.87624C>Ap.Y29208*nonsense
DCM-ES20DB01655 A-bandc.89900_89903delATTAp.N29967fsframeshift
DCM-ES20AA01165 A-bandc.90322_90323insTp.Glu30108*frameshift
DCM-ES20AK01584 A-bandc.93166C>Tp.R31056*nonsense
DCM-ES20JM01785 A-bandc.94562dupC p.Thr31522fsframeshift
DCM-ES20PA01474 A-bandc.96460_96461insAp.T32154fsframeshift
DCM-ES20DS01225 A-bandc.98265_98268dupAACAp.His32757fsframeshift
DCM-ES20LB01523 A-bandc.98299_98300delAGp.R32767fsframeshift
DCM-ES20PS01566 A-bandc.98506C>Tp.R32836*nonsense
DCM-ES20IR01555 A-bandc.100445C>Ap.S33482*nonsense
DCM-ES20JR01203 A-bandc.100445C>Ap.Ser33482*nonsense
DCM-ES20RD01346 M-bandc.101021_101022delGAp.Arg33674fsframeshift
DCM-ES20JM01785 M-bandc.107377+1G>A essential splice site
DCM-REPLLW-II-3 I-bandc.11912G>Ap.Trp3971*nonsense
DCM-REPLBA-III-3 I-bandc.13900G>Tp.Glu4634*nonsense
DCM-REPLL-III-1 I-bandc.14056delp.Thr4686fsframeshift
DCM-REPLP-III-9 I-bandc.41835T>Gp.Tyr13945*nonsense
DCM-REPLFW-II-1 I-bandc.42636delp.Ala14213fsframeshift
DCM-REPLKI-III-2 I-bandc.44284C>Tp.Arg14762*nonsense
DCM-REPLGS-III-1 A-bandc.47142_47143dupGTp.Cys15714*frameshift
DCM-REPLAP-III-4 A-bandc.47692C>Tp.Arg15898*nonsense
DCM-REPLMO-II-2 A-bandc.49458G>Ap.Trp16486*nonsense
DCM-REPLFQ-III-11 A-bandc.56206delAp.Thr18736fsframeshift
DCM-REPLBM-III-25 A-bandc.56834delGp.Gly18945fsframeshift
DCM-REPLAM-III-7 A-bandc.59352delTp.Glu19785fsframeshift
DCM-REPLFM-II-1 A-bandc.59411dupTp.Arg19805fsframeshift
DCM-REPLJR-II-1 A-bandc.61495C>Tp.Arg20499*nonsense
DCM-REPLN-IV-1 A-bandc.65476G>Tp.Glu21826*nonsense
DCM-REPLCS-III-12 A-bandc.69491_69492delTGp.Val23164fsframeshift
DCM-REPLJM-II-4 A-bandc.69877G>Tp.Gly23293*nonsense
DCM-REPLLL-III-1 A-bandc.73109G>Ap.Trp24370*nonsense
DCM-REPLDI-II-6 A-bandc.74883_74884insAACAp.Pro24962fsframeshift
DCM-REPLCT-II-2 A-bandc.76115dupAp.Asn25372fsframeshift
DCM-REPLR-IV-2 A-bandc.76115dupAp.Asn25372fsframeshift
DCM-REPLAV-IV-2 A-bandc.78095_78098delGAAAp.Arg26032fsframeshift
DCM-REPLBR-IV-1 A-bandc.78991C>Tp.Arg26331*nonsense
DCM-REPLEA-II-7 A-bandc.78991C>Tp.Arg26331*nonsense
DCM-REPLLX-III-9 A-bandc.79684C>Tp.Arg26562*nonsense
DCM-REPLIT-II-2 A-bandc.83515C>Tp.Arg27839*nonsense
DCM-REPLLT-II-1 A-bandc.84376C>Tp.Gln28126*nonsense
DCM-REPLEY-III-3 A-bandc.87716delp.Gly29239fsframeshift
DCM-REPLNW-III-1 A-bandc.87887_87890delACTTp.His29296fsframeshift
DCM-REPLAG-III-1 A-bandc.94855C>Tp.Arg31619*nonsense
DCM-REPLEB-III-2 M-bandc.101098_101099insTp.Asp33700fsframeshift
HEALTHY-IC14AG01422 near Z-diskc.3100G>Ap.Val1034Metother splice site
HEALTHY-IC14SS01830 c.10852C>Tp.Gln3618Xnonsense
HEALTHY-IC14JD01896 I-bandc.21142C>Tp.Arg7048Xnonsense
HEALTHY-IC14EC01433 I-bandc.30803-2A>Gessential splice site
HEALTHY-IC14KN01429 I-bandc.32095+5G>Aother splice site
HEALTHY-IC14AH01539 I-bandc.32554+1G>Cessential splice site
HEALTHY-IC14MO01427 I-bandc.45391delAp.Ile15131TyrfsX46frameshift
HEALTHY-IC14JM01448 A-bandc.67159delAp.Ile22387Xframeshift
WHISRR362531 Z-diskc.325C>Tp.Arg109*nonsense
WHISRR377830 c.11183dupGp.Leu3729fsframeshift
WHISRR363549 c.16516G>Tp.Glu5506*nonsense
WHISRR444813 c.16516G>Tp.Glu5506*nonsense
WHISRR485694 c.16516G>Tp.Glu5506*nonsense
WHISRR373048 c.16529delTp.Val5510fsframeshift
WHISRR372890 I-bandc.31762G>Ap.Val10588Ileother splice site
WHISRR363555 I-bandc.31763-1G>Aessential splice site
WHISRR363326 A-bandc.96892C>Tp.Gln32298*nonsense
FHS17431 Z-diskc.1245+3A>Gother splice site
FHS5630 near Z-diskc.3100G>Aother splice site
FHS8864 I-bandc.9727C>Tp.Q3243*nonsense
FHS15956 c.10799C>Ap.S3600*nonsense
FHS12004 c.10852C>Tp.Q3618*nonsense
FHS11278 c.11183_11184insGp.G3728fsframeshift
FHS35 c.10443_10443delAp.K3481fsframeshift
FHS21984 c.13660_13661insAp.I4554fsframeshift
FHS13496 c.13705G>Tp.E4569*nonsense
FHS21368 c.13939_13939delGp.E4647fsframeshift
FHS14608 c.15305_15305delCp.T5102fsframeshift
FHS13791 I-bandc.15776-1G>Tessential splice site
FHS14685 I-bandc.31426+1G>Cessential splice site
FHS530 I-bandc.40558+1G>Aessential splice site
FHS1508 A-bandc.52128_52128delTp.F17376fsframeshift
FHS26653 A-bandc.62506C>Tp.R20836*nonsense
FHS21151 A-bandc.68824G>Aother splice site
FHS9484 A-bandc.80635C>Tp.Q26879*nonsense
FHS19648 A-bandc.87716_87716delGp.G29239fsframeshift
FHS11733 A-bandc.98551C>Tp.R32851*nonsense
FHS21570 A-bandc.98551C>Tp.R32851*nonsense
JHSJ127199 near Z-diskc.2494G>Tother splice site
JHSJ183455 near Z-diskc.2841G>Tother splice site
JHSJ306717 near Z-disk / I-bandc.6355G>Tp.E2119*nonsense
JHSJ544442 I-bandc.9164-2A>Tessential splice site
JHSJ507994 c.10592C>Gp.S3531*nonsense
JHSJ193179 c.11113_11113delAp.R3705fsframeshift
JHSJ503785 c.11113_11113delAp.R3705fsframeshift
JHSJ133254 c.13410_13411insAp.K4470fsframeshift
JHSJ550924 I-bandc.14093-1G>Aessential splice site
JHSJ547288 I-bandc.23386C>Tp.R7796*nonsense
JHSJ120020 I-bandc.27328+5G>Aother splice site
JHSJ226108 I-bandc.27607G>Aother splice site
JHSJ548074 I-bandc.29042-2A>Cessential splice site
JHSJ550083 I-bandc.29042-2A>Cessential splice site
JHSJ558930 I-bandc.29042-2A>Cessential splice site
JHSJ508635 I-bandc.31594G>Tother splice site
JHSJ162495 I-bandc.39895+1G>Tessential splice site
JHSJ206585 A-bandc.48460+5G>Aother splice site
JHSJ510863 A-bandc.48460+5G>Aother splice site
JHSJ554679 A-bandc.48460+5G>Aother splice site
JHSJ560750 A-bandc.48460+5G>Aother splice site
JHSJ506451 A-bandc.68824G>Aother splice site
JHSJ578580 A-bandc.75123T>Ap.Y25041*nonsense
JHSJ545511 A-bandc.85008_85011delTAGTp.V28336fsframeshift
JHSJ550577 A-bandc.91715_91716insAp.N30572fsframeshift
JHSJ545771 A-bandc.92288_92289insAAAAGp.S30763fsframeshift
JHSJ567853 A-bandc.92288_92289insAAAAGp.S30763fsframeshift
JHSJ154955 A-bandc.97192+4A>Gother splice site
JHSJ541798 M-bandc.102630_102630delAp.K34210fsframeshift
JHSJ542193 M-bandc.103408G>Tp.E34470*nonsense
JHSJ316117 M-bandc.104092C>Tp.R34698*nonsense
JHSJ551172 M-bandc.106374+1delGessential splice site