BibTex format
@article{Perotto:2026:10.1161/CIRCGEN.125.005422,
author = {Perotto, M and Radesich, C and Paldino, A and Gandin, I and Verdonschot, JAJ and Kim, Y and Balakrishnan, ID and Stroekes, S and Medo, K and Gigli, M and Lenarduzzi, S and Girotto, G and Claggett, B and Ammirati, E and Barison, A and Bertero, E and Biagini, E and Canepa, M and Carugo, S and Day, S and Ditaranto, R and Faggiano, A and Fornaro, A and Forleo, C and Gentile, P and Guaricci, AI and Helms, AS and Ho, CY and Iascone, M and Iorio, A and Khan, SS and Lin, K and Mestroni, L and Olivotto, I and Owens, A and Ribichini, FL and Rossano, J and Shore, S and Setti, M and Wheeler, M and Taylor, MRG and Wilsbacher, L and Tayal, U and Parikh, VN and Heymans, S and Prasad, S and Italian, TTN Consortium and DCMAC SHaRe Consortium and Sinagra, G and Merlo, M and Lakdawala, NK and Dal, Ferro M},
doi = {10.1161/CIRCGEN.125.005422},
journal = {Circ Genom Precis Med},
title = {Variant Site-Specific Natural History of Titin-Induced Cardiomyopathy: An International Multicenter Registry.},
url = {http://dx.doi.org/10.1161/CIRCGEN.125.005422},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - BACKGROUND: Titin truncating variants (TTNtv) represent the most common genotype underlying dilated cardiomyopathy but are also detected in the general population, exhibiting incomplete penetrance and marked phenotypic variability. This heterogeneity complicates clinical interpretation and risk stratification. Emerging molecular evidence suggests that truncating location within the gene may influence disease mechanisms. We aimed to investigate whether TTNtv location also affects clinical phenotype and prognosis. METHODS: We established an international multicenter registry of phenotypically affected carriers of pathogenic or likely pathogenic TTNtv. Patients were classified into 3 groups: A-band, Z/I-band, and M-band. A case-control study assessed the enrichment of TTNtv across regions. The primary outcome was a composite of all-cause mortality and heart transplantation. Secondary outcomes included: (1) sudden cardiac death or major ventricular arrhythmias and (2) heart failure-related death/heart transplantation/left ventricular assist device implantation. RESULTS: The study included 467 patients (81% probands, 73% male, median age 47 years, 81% dilated cardiomyopathy phenotype). Most carried TTNtv in the A-band (80% versus 15% Z/I-band and 5% M-band). All groups showed enrichment compared with GnomAD, with greater Bayesian-estimated penetrance for A-band variants. Over a median follow-up of 83 months, the primary end point was similar across groups. However, the risk of sudden cardiac death/major ventricular arrhythmias was significantly higher in M-band carriers (45% M-band versus 23% Z/I-band versus 12% A-band; P=0.001), especially as the first disease manifestation. Band location independently predicted sudden cardiac death/major ventricular arrhythmias risk, whereas left ventricular ejection fraction was predictive only in A- and Z/I-band groups. CONCLUSIONS: TTNtv are differently enriched across the gene in patients with dilated cardiomyopathy/nondilated left
AU - Perotto,M
AU - Radesich,C
AU - Paldino,A
AU - Gandin,I
AU - Verdonschot,JAJ
AU - Kim,Y
AU - Balakrishnan,ID
AU - Stroekes,S
AU - Medo,K
AU - Gigli,M
AU - Lenarduzzi,S
AU - Girotto,G
AU - Claggett,B
AU - Ammirati,E
AU - Barison,A
AU - Bertero,E
AU - Biagini,E
AU - Canepa,M
AU - Carugo,S
AU - Day,S
AU - Ditaranto,R
AU - Faggiano,A
AU - Fornaro,A
AU - Forleo,C
AU - Gentile,P
AU - Guaricci,AI
AU - Helms,AS
AU - Ho,CY
AU - Iascone,M
AU - Iorio,A
AU - Khan,SS
AU - Lin,K
AU - Mestroni,L
AU - Olivotto,I
AU - Owens,A
AU - Ribichini,FL
AU - Rossano,J
AU - Shore,S
AU - Setti,M
AU - Wheeler,M
AU - Taylor,MRG
AU - Wilsbacher,L
AU - Tayal,U
AU - Parikh,VN
AU - Heymans,S
AU - Prasad,S
AU - Italian,TTN Consortium and DCMAC SHaRe Consortium
AU - Sinagra,G
AU - Merlo,M
AU - Lakdawala,NK
AU - Dal,Ferro M
DO - 10.1161/CIRCGEN.125.005422
PY - 2026///
TI - Variant Site-Specific Natural History of Titin-Induced Cardiomyopathy: An International Multicenter Registry.
T2 - Circ Genom Precis Med
UR - http://dx.doi.org/10.1161/CIRCGEN.125.005422
UR - https://www.ncbi.nlm.nih.gov/pubmed/42417033
ER -