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.
Cohort | Description | Status | Size | TTNtv % |
---|---|---|---|---|
DCM-PRO | Prospective DCM patients from Royal Brompton Hospital | DCM | 374 | 14.4% |
DCM-ES * | End-stage non-ischemic DCM patients from Harefield Hospital | DCM | 155 | 24.5% |
DCM-REPL | Replication DCM cohort from St Vincent's Hospital and Victor Chang Cardiovascular Institute | DCM | 163 | 19.0% |
HEALTHY-IC | Clinically screened healthy controls recruited from Imperial College, London | HEALTHY | 308 | 2.6% |
WHI | Replication control cohort from The Women's Health Initiative (WHI) | CONTROL | 667 | 1.3% |
FHS | Participants in the Framingham Heart Study (FHS) Offspring Cohort, European ancestry | CONTROL | 1623 | 1.3% |
JHS | Random participants in the Jackson Heart Study (JHS), African-American population | CONTROL | 1980 | 1.6% |
* Please note 71 of these patients were also included in DCM-B cohort from the 2012 NEJM study.
Cohort | Patient ID | Exon | Band | Variant (CDS) | Variant (protein) | Variant Type |
---|---|---|---|---|---|---|
DCM-PRO | 10AP01669 | 27 | near Z-disk | c.4724_4728delTGAAA | p.Met1575SerfsX6 | frameshift |
DCM-PRO | 10RW00786 | 35 | I-band | c.8307_8308delTG | p.Ala2770HisfsX4 | frameshift |
DCM-PRO | 12FB00047 | 48 | c.13022C>G | p.Ser4341X | nonsense | |
DCM-PRO | 10DW00512 | 49 | I-band | c.12643_12644delCA | p.Gln4215ValfsX16 | frameshift |
DCM-PRO | 14MW01583 | 49 | I-band | c.12757C>T | p.Gln4253X | nonsense |
DCM-PRO | 10GG01869 | 96 | I-band | c.27607G>A | p.Glu9203Lys | other splice site |
DCM-PRO | 10JF01835 | 102 | I-band | c.29042-2A>C | essential splice site | |
DCM-PRO | 12SK00375 | 102 | I-band | c.29062delG | p.Ala9688GlnfsX7 | frameshift |
DCM-PRO | 12PB00376 | 123 | I-band | c.31763-1G>A | essential splice site | |
DCM-PRO | 10SB00367 | 136 | I-band | c.32888-1delG | essential splice site | |
DCM-PRO | 12MD01102 | 140 | I-band | c.33418+1G>A | essential splice site | |
DCM-PRO | 12MA01291 | 203 | I-band | c.39044-9T>A | other splice site | |
DCM-PRO | 10RC00179 | 227 | I-band | c.41447delG | p.Gly13816AlafsX18 | frameshift |
DCM-PRO | 10PC00581 | 227 | I-band | c.41473C>T | p.Arg13825X | nonsense |
DCM-PRO | 10JM01592 | 238 | I-band | c.43792delG | p.Val14598X | frameshift |
DCM-PRO | 10BC00144 | 248 | I-band | c.45756dupA | p.Tyr15253IlefsX15 | frameshift |
DCM-PRO | 10WS00448 | 248 | I-band | c.45812T>G | p.Leu15271X | nonsense |
DCM-PRO | 10VS00240 | 255 | A-band | c.47697C>A | p.Cys15899X | nonsense |
DCM-PRO | 10DR00069 | 256 | A-band | c.47875+1G>A | essential splice site | |
DCM-PRO | 10CH00929 | 260 | A-band | c.48527G>A | p.Trp16176X | nonsense |
DCM-PRO | 10JN00724 | 267 | A-band | c.50170C>T | p.Arg16724X | nonsense |
DCM-PRO | 10LP00987 | 267 | A-band | c.50170C>T | p.Arg16724X | nonsense |
DCM-PRO | 10RN00513 | 267 | A-band | c.50170C>T | p.Arg16724X | nonsense |
DCM-PRO | 10LB00067 | 274 | A-band | c.52035_52036insTT | p.Leu17346PhefsX4 | frameshift |
DCM-PRO | 10DH00882 | 275 | A-band | c.52223_52227dupAGAAA | p.Asp17410ArgfsX25 | frameshift |
DCM-PRO | 12AM00400 | 280 | A-band | c.53881+1G>T | essential splice site | |
DCM-PRO | 10JS00726 | 280 | A-band | c.53881+5G>A | other splice site | |
DCM-PRO | 10HH00944 | 287 | A-band | c.55303-1G>A | essential splice site | |
DCM-PRO | 10JF01881 | 288 | A-band | c.55525_55531delGACAGGA | p.Asp18509SerfsX29 | frameshift |
DCM-PRO | 10SF00976 | 288 | A-band | c.55525_55531delGACAGGA | p.Asp18509SerfsX29 | frameshift |
DCM-PRO | 10RN00513 | 295 | A-band | c.57544+4A>G | other splice site | |
DCM-PRO | 10AL00811 | 299 | A-band | c.58732+2T>C | essential splice site | |
DCM-PRO | 12SR01222 | 305 | A-band | c.60931C>T | p.Arg20311X | nonsense |
DCM-PRO | 10TM00933 | 305 | A-band | c.63025C>T | p.Arg21009X | nonsense |
DCM-PRO | 10CS01472 | 326 | A-band | c.69630C>A | p.Tyr23210X | nonsense |
DCM-PRO | 12JL01327 | 327 | A-band | c.74306dupA | p.Asn24769LysfsX2 | frameshift |
DCM-PRO | 10BK01803 | 327 | A-band | c.78184G>T | p.Glu26062X | nonsense |
DCM-PRO | 10JC00262 | 327 | A-band | c.78507delT | p.Gly26170ValfsX3 | frameshift |
DCM-PRO | 10DM00077 | 327 | A-band | c.81262_81269delCAGATGCT | p.Gln27088CysfsX5 | frameshift |
DCM-PRO | 10PP00413 | 327 | A-band | c.81262_81269delCAGATGCT | p.Gln27088CysfsX5 | frameshift |
DCM-PRO | 12NP00167 | 327 | A-band | c.81321C>G | p.Tyr27107X | nonsense |
DCM-PRO | 10CP00605 | 327 | A-band | c.82513delA | p.Ile27505PhefsX20 | frameshift |
DCM-PRO | 10PP00465 | 327 | A-band | c.85090C>T | p.Arg28364X | nonsense |
DCM-PRO | 12MH00114 | 327 | A-band | c.86640delC | p.His28881ThrfsX2 | frameshift |
DCM-PRO | 12JL00046 | 328 | A-band | c.86967G>A | p.Trp28989X | nonsense |
DCM-PRO | 12ML01299 | 330 | A-band | c.87716delG | p.Gly29239AspfsX32 | frameshift |
DCM-PRO | 10MV00215 | 336 | A-band | c.89750dupG | p.Val29918SerfsX3 | frameshift |
DCM-PRO | 10TD00812 | 336 | A-band | c.90086_90088delAAGinsA | p.Glu30029AspfsX7 | frameshift |
DCM-PRO | 10KF00073 | 340 | A-band | c.92683C>T | p.Arg30895X | nonsense |
DCM-PRO | 10AG01687 | 343 | A-band | c.94849_94855delGATGCCC | p.Ala31618TyrfsX37 | frameshift |
DCM-PRO | 10KW01906 | 344 | A-band | c.95415_95416+2delCAGT | essential splice site | |
DCM-PRO | 10CS01784 | 353 | A-band | c.98265_98268dupAACA | p.His32757AsnfsX4 | frameshift |
DCM-PRO | 14CT01557 | 359 | M-band | c.101996G>A | p.Trp33999X | nonsense |
DCM-PRO | 12PF00041 | 361 | M-band | c.106629delA | p.Ala35544ProfsX2 | frameshift |
DCM-ES | 20HS01530 | 18 | near Z-disk | c.3100G>A | p.Val1034Met | other splice site |
DCM-ES | 20SF01658 | 18 | near Z-disk | c.3100G>A | p.Val1034Met | other splice site |
DCM-ES | 20AH01746 | 18 | near Z-disk | c.3100G>A | p.Val1034Met | other splice site |
DCM-ES | 20JL01558 | 48 | c.14470_14471insCACACTCCATA | p.R4824fs | frameshift | |
DCM-ES | 20VW01643 | 220 | I-band | c.40558G>C | p.Val13520Leu | other splice site |
DCM-ES | 20JT01288 | 240 | I-band | c.44281C>T | p.Pro14761Ser | other splice site |
DCM-ES | 20MC01968 | 240 | I-band | c.44281+1G>A | essential splice site | |
DCM-ES | 20SG01639 | 249 | I-band | c.46236C>A | p.C15412* | nonsense |
DCM-ES | 20JH01781 | 252 | I-band | c.46782C>A | p.Tyr15594* | nonsense |
DCM-ES | 20JB01501 | 264 | A-band | c.49346-1G>A | essential splice site | |
DCM-ES | 20RD01430 | 267 | A-band | c.50247_50247delT | p.F16749fs | frameshift |
DCM-ES | 20JL01448 | 279 | A-band | c.53488G>T | p.G17830* | nonsense |
DCM-ES | 20PD01505 | 298 | A-band | c.58172delA | p.Asp19391fs | frameshift |
DCM-ES | 20VW01643 | 303 | A-band | c.59627-1G>A | essential splice site | |
DCM-ES | 20EG01127 | 307 | A-band | c.63601C>T | p.Arg21201* | nonsense |
DCM-ES | 20SW01468 | 310 | A-band | c.64453C>T | p.R21485* | nonsense |
DCM-ES | 20JD01577 | 320 | A-band | c.67495C>T | p.R22499* | nonsense |
DCM-ES | 20PS01433 | 325 | A-band | c.69412+1G>A | essential splice site | |
DCM-ES | 20CW01447 | 327 | A-band | c.69843_69843delA | p.K23281fs | frameshift |
DCM-ES | 20HS01530 | 327 | A-band | c.70791_70791delA | p.E23597fs | frameshift |
DCM-ES | 20FG01148 | 327 | A-band | c.74338C>T | p.Arg24780* | nonsense |
DCM-ES | 20SF01123 | 327 | A-band | c.76116_76117insA | p.Asn25372fs | frameshift |
DCM-ES | 20SB01532 | 327 | A-band | c.76383_76386delTAAT | p.Asn25462fs | frameshift |
DCM-ES | 20DH01701 | 327 | A-band | c.81518delC | p.Pro27173fs | frameshift |
DCM-ES | 20LN01500 | 327 | A-band | c.86459_86460delCT | p.S28820fs | frameshift |
DCM-ES | 20BM01499 | 329 | A-band | c.87624C>A | p.Y29208* | nonsense |
DCM-ES | 20DB01655 | 336 | A-band | c.89900_89903delATTA | p.N29967fs | frameshift |
DCM-ES | 20AA01165 | 336 | A-band | c.90322_90323insT | p.Glu30108* | frameshift |
DCM-ES | 20AK01584 | 340 | A-band | c.93166C>T | p.R31056* | nonsense |
DCM-ES | 20JM01785 | 342 | A-band | c.94562dupC | p.Thr31522fs | frameshift |
DCM-ES | 20PA01474 | 348 | A-band | c.96460_96461insA | p.T32154fs | frameshift |
DCM-ES | 20DS01225 | 353 | A-band | c.98265_98268dupAACA | p.His32757fs | frameshift |
DCM-ES | 20LB01523 | 353 | A-band | c.98299_98300delAG | p.R32767fs | frameshift |
DCM-ES | 20PS01566 | 353 | A-band | c.98506C>T | p.R32836* | nonsense |
DCM-ES | 20IR01555 | 358 | A-band | c.100445C>A | p.S33482* | nonsense |
DCM-ES | 20JR01203 | 358 | A-band | c.100445C>A | p.Ser33482* | nonsense |
DCM-ES | 20RD01346 | 359 | M-band | c.101021_101022delGA | p.Arg33674fs | frameshift |
DCM-ES | 20JM01785 | 362 | M-band | c.107377+1G>A | essential splice site | |
DCM-REPL | LW-II-3 | 49 | I-band | c.11912G>A | p.Trp3971* | nonsense |
DCM-REPL | BA-III-3 | 49 | I-band | c.13900G>T | p.Glu4634* | nonsense |
DCM-REPL | L-III-1 | 49 | I-band | c.14056del | p.Thr4686fs | frameshift |
DCM-REPL | P-III-9 | 228 | I-band | c.41835T>G | p.Tyr13945* | nonsense |
DCM-REPL | FW-II-1 | 232 | I-band | c.42636del | p.Ala14213fs | frameshift |
DCM-REPL | KI-III-2 | 241 | I-band | c.44284C>T | p.Arg14762* | nonsense |
DCM-REPL | GS-III-1 | 253 | A-band | c.47142_47143dupGT | p.Cys15714* | frameshift |
DCM-REPL | AP-III-4 | 255 | A-band | c.47692C>T | p.Arg15898* | nonsense |
DCM-REPL | MO-II-2 | 264 | A-band | c.49458G>A | p.Trp16486* | nonsense |
DCM-REPL | FQ-III-11 | 290 | A-band | c.56206delA | p.Thr18736fs | frameshift |
DCM-REPL | BM-III-25 | 292 | A-band | c.56834delG | p.Gly18945fs | frameshift |
DCM-REPL | AM-III-7 | 302 | A-band | c.59352delT | p.Glu19785fs | frameshift |
DCM-REPL | FM-II-1 | 302 | A-band | c.59411dupT | p.Arg19805fs | frameshift |
DCM-REPL | JR-II-1 | 305 | A-band | c.61495C>T | p.Arg20499* | nonsense |
DCM-REPL | N-IV-1 | 313 | A-band | c.65476G>T | p.Glu21826* | nonsense |
DCM-REPL | CS-III-12 | 326 | A-band | c.69491_69492delTG | p.Val23164fs | frameshift |
DCM-REPL | JM-II-4 | 327 | A-band | c.69877G>T | p.Gly23293* | nonsense |
DCM-REPL | LL-III-1 | 327 | A-band | c.73109G>A | p.Trp24370* | nonsense |
DCM-REPL | DI-II-6 | 327 | A-band | c.74883_74884insAACA | p.Pro24962fs | frameshift |
DCM-REPL | CT-II-2 | 327 | A-band | c.76115dupA | p.Asn25372fs | frameshift |
DCM-REPL | R-IV-2 | 327 | A-band | c.76115dupA | p.Asn25372fs | frameshift |
DCM-REPL | AV-IV-2 | 327 | A-band | c.78095_78098delGAAA | p.Arg26032fs | frameshift |
DCM-REPL | BR-IV-1 | 327 | A-band | c.78991C>T | p.Arg26331* | nonsense |
DCM-REPL | EA-II-7 | 327 | A-band | c.78991C>T | p.Arg26331* | nonsense |
DCM-REPL | LX-III-9 | 327 | A-band | c.79684C>T | p.Arg26562* | nonsense |
DCM-REPL | IT-II-2 | 327 | A-band | c.83515C>T | p.Arg27839* | nonsense |
DCM-REPL | LT-II-1 | 327 | A-band | c.84376C>T | p.Gln28126* | nonsense |
DCM-REPL | EY-III-3 | 330 | A-band | c.87716del | p.Gly29239fs | frameshift |
DCM-REPL | NW-III-1 | 330 | A-band | c.87887_87890delACTT | p.His29296fs | frameshift |
DCM-REPL | AG-III-1 | 343 | A-band | c.94855C>T | p.Arg31619* | nonsense |
DCM-REPL | EB-III-2 | 359 | M-band | c.101098_101099insT | p.Asp33700fs | frameshift |
HEALTHY-IC | 14AG01422 | 18 | near Z-disk | c.3100G>A | p.Val1034Met | other splice site |
HEALTHY-IC | 14SS01830 | 46 | c.10852C>T | p.Gln3618X | nonsense | |
HEALTHY-IC | 14JD01896 | 74 | I-band | c.21142C>T | p.Arg7048X | nonsense |
HEALTHY-IC | 14EC01433 | 115 | I-band | c.30803-2A>G | essential splice site | |
HEALTHY-IC | 14KN01429 | 126 | I-band | c.32095+5G>A | other splice site | |
HEALTHY-IC | 14AH01539 | 131 | I-band | c.32554+1G>C | essential splice site | |
HEALTHY-IC | 14MO01427 | 247 | I-band | c.45391delA | p.Ile15131TyrfsX46 | frameshift |
HEALTHY-IC | 14JM01448 | 319 | A-band | c.67159delA | p.Ile22387X | frameshift |
WHI | SRR362531 | 4 | Z-disk | c.325C>T | p.Arg109* | nonsense |
WHI | SRR377830 | 46 | c.11183dupG | p.Leu3729fs | frameshift | |
WHI | SRR363549 | 48 | c.16516G>T | p.Glu5506* | nonsense | |
WHI | SRR444813 | 48 | c.16516G>T | p.Glu5506* | nonsense | |
WHI | SRR485694 | 48 | c.16516G>T | p.Glu5506* | nonsense | |
WHI | SRR373048 | 48 | c.16529delT | p.Val5510fs | frameshift | |
WHI | SRR372890 | 122 | I-band | c.31762G>A | p.Val10588Ile | other splice site |
WHI | SRR363555 | 123 | I-band | c.31763-1G>A | essential splice site | |
WHI | SRR363326 | 348 | A-band | c.96892C>T | p.Gln32298* | nonsense |
FHS | 17431 | 7 | Z-disk | c.1245+3A>G | other splice site | |
FHS | 5630 | 18 | near Z-disk | c.3100G>A | other splice site | |
FHS | 8864 | 42 | I-band | c.9727C>T | p.Q3243* | nonsense |
FHS | 15956 | 46 | c.10799C>A | p.S3600* | nonsense | |
FHS | 12004 | 46 | c.10852C>T | p.Q3618* | nonsense | |
FHS | 11278 | 46 | c.11183_11184insG | p.G3728fs | frameshift | |
FHS | 35 | 48 | c.10443_10443delA | p.K3481fs | frameshift | |
FHS | 21984 | 48 | c.13660_13661insA | p.I4554fs | frameshift | |
FHS | 13496 | 48 | c.13705G>T | p.E4569* | nonsense | |
FHS | 21368 | 48 | c.13939_13939delG | p.E4647fs | frameshift | |
FHS | 14608 | 48 | c.15305_15305delC | p.T5102fs | frameshift | |
FHS | 13791 | 55 | I-band | c.15776-1G>T | essential splice site | |
FHS | 14685 | 118 | I-band | c.31426+1G>C | essential splice site | |
FHS | 530 | 220 | I-band | c.40558+1G>A | essential splice site | |
FHS | 1508 | 275 | A-band | c.52128_52128delT | p.F17376fs | frameshift |
FHS | 26653 | 305 | A-band | c.62506C>T | p.R20836* | nonsense |
FHS | 21151 | 324 | A-band | c.68824G>A | other splice site | |
FHS | 9484 | 327 | A-band | c.80635C>T | p.Q26879* | nonsense |
FHS | 19648 | 330 | A-band | c.87716_87716delG | p.G29239fs | frameshift |
FHS | 11733 | 353 | A-band | c.98551C>T | p.R32851* | nonsense |
FHS | 21570 | 353 | A-band | c.98551C>T | p.R32851* | nonsense |
JHS | J127199 | 16 | near Z-disk | c.2494G>T | other splice site | |
JHS | J183455 | 17 | near Z-disk | c.2841G>T | other splice site | |
JHS | J306717 | 28 | near Z-disk / I-band | c.6355G>T | p.E2119* | nonsense |
JHS | J544442 | 39 | I-band | c.9164-2A>T | essential splice site | |
JHS | J507994 | 45 | c.10592C>G | p.S3531* | nonsense | |
JHS | J193179 | 46 | c.11113_11113delA | p.R3705fs | frameshift | |
JHS | J503785 | 46 | c.11113_11113delA | p.R3705fs | frameshift | |
JHS | J133254 | 48 | c.13410_13411insA | p.K4470fs | frameshift | |
JHS | J550924 | 50 | I-band | c.14093-1G>A | essential splice site | |
JHS | J547288 | 82 | I-band | c.23386C>T | p.R7796* | nonsense |
JHS | J120020 | 95 | I-band | c.27328+5G>A | other splice site | |
JHS | J226108 | 96 | I-band | c.27607G>A | other splice site | |
JHS | J548074 | 102 | I-band | c.29042-2A>C | essential splice site | |
JHS | J550083 | 102 | I-band | c.29042-2A>C | essential splice site | |
JHS | J558930 | 102 | I-band | c.29042-2A>C | essential splice site | |
JHS | J508635 | 120 | I-band | c.31594G>T | other splice site | |
JHS | J162495 | 212 | I-band | c.39895+1G>T | essential splice site | |
JHS | J206585 | 259 | A-band | c.48460+5G>A | other splice site | |
JHS | J510863 | 259 | A-band | c.48460+5G>A | other splice site | |
JHS | J554679 | 259 | A-band | c.48460+5G>A | other splice site | |
JHS | J560750 | 259 | A-band | c.48460+5G>A | other splice site | |
JHS | J506451 | 324 | A-band | c.68824G>A | other splice site | |
JHS | J578580 | 327 | A-band | c.75123T>A | p.Y25041* | nonsense |
JHS | J545511 | 327 | A-band | c.85008_85011delTAGT | p.V28336fs | frameshift |
JHS | J550577 | 338 | A-band | c.91715_91716insA | p.N30572fs | frameshift |
JHS | J545771 | 340 | A-band | c.92288_92289insAAAAG | p.S30763fs | frameshift |
JHS | J567853 | 340 | A-band | c.92288_92289insAAAAG | p.S30763fs | frameshift |
JHS | J154955 | 349 | A-band | c.97192+4A>G | other splice site | |
JHS | J541798 | 359 | M-band | c.102630_102630delA | p.K34210fs | frameshift |
JHS | J542193 | 359 | M-band | c.103408G>T | p.E34470* | nonsense |
JHS | J316117 | 359 | M-band | c.104092C>T | p.R34698* | nonsense |
JHS | J551172 | 359 | M-band | c.106374+1delG | essential splice site |