Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy.
Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM.



We compared clinical data on DCM probands and relatives with a tTTN mutation (n = 45, n = 73), LMNA mutation (n = 28, n = 29), and probands who tested negative for both genes [idiopathic DCM (iDCM); n = 60]. Median follow-up was at least 2.5 years in each group. TTN subjects presented with DCM at higher age than LMNA subjects (probands 47.9 vs. 40.4 years, P = 0.004; relatives 59.8 vs. 47.0 years, P = 0.01), less often developed LVEF <35% [probands hazard ratio (HR) 0.38, P = 0.002], had higher age of death (probands 70.4 vs. 59.4 years, P < 0.001; relatives 74.1 vs. 58.4 years, P = 0.008), and had better composite outcome (malignant ventricular arrhythmia, heart transplantation, or death; probands HR 0.09, P < 0.001; relatives HR 0.21, P = 0.02) than LMNA subjects and iDCM subjects (HR 0.36, P = 0.07). An LVEF increase of at least 10% occurred in 46.9% of TTN subjects after initiation of standard heart failure treatment, while this only occurred in 6.5% of LMNA subjects (P < 0.001) and 18.5% of iDCM subjects (P = 0.02). This was confirmed in families with co-segregation, in which the 10% point LVEF increase occurred in 55.6% of subjects (P = 0.003 vs. LMNA, P = 0.079 vs. iDCM).



This study shows that tTTN-associated DCM is less severe at presentation and more amenable to standard therapy than LMNA mutation-induced DCM or iDCM.
AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Joeri A
JA
Jansweijer
Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Karin
K
Nieuwhof
Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Francesco
F
Russo
Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Edgar T
ET
Hoorntje
Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Jan D H
JD
Jongbloed
Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Ronald H
RH
Lekanne Deprez
Department of Anatomy, Embryology and Physiology, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Alex V
AV
Postma
Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Marieke
M
Bronk
AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Ingrid A W
IA
van Rijsingen
Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Simone
S
de Haij
Department of Cardiology, S. Orsola-Malpighi Hospital, Bologna University, Italy.
Elena
E
Biagini
Department of Cardiology, Antonius Hospital, Sneek, The Netherlands.
Paul L
PL
van Haelst
Department of Cardiology, Deventer Hospital, Deventer, The Netherlands.
Jan
J
van Wijngaarden
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Maarten P
MP
van den Berg
AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Arthur A M
AA
Wilde
Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Marcel M A M
MM
Mannens
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Rudolf A
RA
de Boer
Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Karin Y
KY
van Spaendonck-Zwarts
Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
J Peter
JP
van Tintelen
AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
Yigal M
YM
Pinto
D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D016022:Case-Control Studies; D064211:Connectin / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006333:Heart Failure / Q000235:genetics / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D034904:Lamin Type A / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013318:Stroke Volume
D064211:Connectin; C494847:LMNA protein, human; D034904:Lamin Type A; C577285:TTN protein, human
Diagnosis; Dilated cardiomyopathy; Gene; Prognosis; Treatment