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Vol. 69. Issue 2.
Pages 149-158 (February 2016)
Original article
DOI: 10.1016/j.rec.2015.06.025
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Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene
Perfil clínico y pronóstico de las miocardiopatías causadas por mutaciones en el gen de la troponina T
Tomás Ripoll-Veraa,
Corresponding author

Corresponding author: Servicio de Cardiología, Hospital Son Llàtzer, Ctra. Manacor Km. 4, 07198 Palma de Mallorca, Balearic Islands, Spain.
, José María Gámeza, Nancy Goveab, Yolanda Gómeza, Juana Núñeza, Lorenzo Socíasa, Ángela Escandella, Jorge Rosellb
a Servicio de Cardiología, Hospital Son Llàtzer, IdISPa, Ciberobn, Palma de Mallorca, Balearic Islands, Spain
b Sección de Genética, Hospital Son Espases, Palma de Mallorca, Balearic Islands, Spain
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Tables (3)
Table 1. Clinical and Genetic Data on Patients and Families Included in the Study
Table 2. Clinical, Echocardiographic, and Prognostic Characteristics of Patients with Cardiomyopathy According to the TNNT2 Mutation
Table 3. Published Studies on Survival With Mutations in the TNNT2 Gene
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Introduction and aims

Mutations in the troponin T gene (TTNT2) have been associated in small studies with the development of hypertrophic cardiomyopathy characterized by a high risk of sudden death and mild hypertrophy. We describe the clinical course of patients carrying mutations in this gene.


We analyzed the clinical characteristics and prognosis of patients with mutations in the TNNT2 gene who were seen in an inherited cardiac disease unit.


Of 180 families with genetically studied cardiomyopathies, 21 families (11.7%) were identified as having mutations in TNNT2: 10 families had Arg92Gln, 5 had Arg286His, 3 had Arg278Cys, 1 had Arg92Trp, 1 had Arg94His, and 1 had Ile221Thr. Thirty-three additional genetic carriers were identified through family assessment. The study included 54 genetic carriers: 56% were male, and the mean average age was 41 ± 17 years. There were 33 cases of hypertrophic cardiomyopathy, 9 of dilated cardiomyopathy, and 1 of noncompaction cardiomyopathy, and maximal myocardial thickness was 18.5 ± 6mm. Ventricular dysfunction was present in 30% of individuals and a history of sudden death in 62%. During follow-up, 4 patients died and 14 (33%) received a defibrillator (8 probands, 6 relatives). Mean survival was 54 years. Carriers of Arg92Gln had early disease development, high penetrance, a high risk of sudden death, a high rate of defibrillator implantation, and a high frequency of mixed phenotype.


Mutations in the TNNT2 gene were more common in this series than in previous studies. The clinical and prognostic profiles depended on the mutation present. Carriers of the Arg92Gln mutation developed hypertrophic or dilated cardiomyopathy and had a significantly worse prognosis than those with other mutations in TNNT2 or other sarcomeric genes.

Genetic mutation
Heart failure
Sudden death
Introducción y objetivos

Las mutaciones en el gen de la troponina T (TNNT2) se han asociado en pequeños estudios al desarrollo de miocardiopatía hipertrófica caracterizada por alto riesgo de muerte súbita e hipertrofia leve. Se describe el curso clínico de los pacientes portadores de mutaciones en este gen.


Se analizaron las características clínicas y el pronóstico de los sujetos con mutaciones en el gen TNNT2 atendidos en una unidad de cardiopatías familiares.


A partir de 180 familias con miocardiopatías estudiadas genéticamente, se identificó a 21 (11,7%) con mutaciones en TNNT2: 10 familias Arg92Gln, 5 Arg286His, 3 Arg278Cys, 1 Arg92Trp, 1 Arg94His y 1 Ile221Thr. A través de la evaluación familiar se identificó a 33 portadores genéticos adicionales. El estudio incluyó a 54 portadores genéticos: el 56% varones con una media de edad de 41±17 años; 33 miocardiopatías hipertróficas, 9 dilatadas y 1 no compactada, con grosor máximo de 18,5±6mm; con disfunción ventricular el 30% y antecedentes de muerte súbita el 62%. En el seguimiento 4 fallecieron y 14 (33%) recibieron un desfibrilador (8 probandos, 6 familiares). La supervivencia media fue de 54 años. Los portadores de Arg92Gln tuvieron desarrollo precoz, alta penetrancia, alto riesgo de muerte súbita, alta tasa de implante de desfibrilador y alta frecuencia de fenotipo mixto.


Las mutaciones en el gen TNNT2 fueron más frecuentes en esta serie. Su perfil clínico y pronóstico depende de la mutación hallada. Los portadores de la mutación Arg92Gln desarrollaron miocardiopatía hipertrófica o dilatada y tuvieron un pronóstico significativamente peor que con otras mutaciones en TNNT2 u otros genes sarcoméricos.

Palabras clave:
Mutación génica
Insuficiencia cardiaca
Muerte súbita
Full Text

Hypertrophic cardiomyopathy (HCM) is an inherited autosomal-dominant disease with a heterogeneous clinical presentation and natural history,1 and is a frequent cause of sudden cardiac death (SCD) in young people2–4; it is associated with mutations in genes coding for sarcomere proteins.5–7 In the literature, debate surrounds the genotype-phenotype correlation of individual mutations,7,8 concerning establishing a prognosis according to the mutation present, which could help stratify the disease and allow appropriate genetic counselling to families. Mutations in the troponin T gene (TNNT2) were described years ago in several publications with few families, and researchers postulated a high prevalence of SCD in young carriers5,6,9,10 who, in addition, had a phenotype of mild left ventricular hypertrophy.6,11

This study aimed to describe the clinical course of a series of patients and relatives—a relatively large series considering the low prevalence of the disease—who were carriers of mutations in TNNT2 and to expand existing knowledge on their prognosis.


The cohort was made up of apparently unrelated probands with cardiomyopathy, most with an HCM phenotype. They were assessed in a familial heart disease clinic in Hospital Son Llàtzer (Palma de Mallorca, Balearic Islands, Spain) over a 7-year period, undergoing genetic study of mutations in the TNNT2 gene (and 4 other sarcomeric genes: MYBPC3, MYH7, TNNI3, and TPM1, as well as lamin A/C if the proband had a dilated cardiomyopathy [DCM] phenotype). All relatives of carriers were offered clinical and genetic assessment.

Hypertrophic cardiomyopathy was diagnosed when the maximal myocardial thickness (MMT) was ≥ 15mm in at least 1 segment in the absence of other diseases to explain the hypertrophy.12,13 In probands with SCD as the first clinical manifestation, the diagnosis of HCM was confirmed at autopsy whenever possible. Relatives were considered affected when they met the HCM familial criteria (≥ 13mm).14

All patients and relatives underwent electrocardiography, echocardiography, stress testing, and 24hours Holter monitoring, as per the methods described,15 as well as cardiac magnetic resonance whenever possible.

The main risk factors for SCD were defined as a family history of SCD, syncopal episode of arrhythmic origin or unknown etiology, nonsustained ventricular tachycardia ≥ 120 bpm, MMT ≥ 30mm and abnormal blood pressure response to exercise (in those younger than 40 years).16

The TNNT2 gene was sequenced with Sanger sequencing or next generation sequencing (NGS). Of 21 probands, 19 were studied using Sanger (the 5 main sarcomeric genes were sequenced: MYBPC3, MYH7, TNNT2, TNNI3, and TPM1) and 2 were studied with NGS (in one patient, 12 genes: the 5 sarcomeric genes plus ACTC1, GLA, MYL2, MYL3, PRKAG2, PTPN11, and TNNC1, and in the other patient, 27 genes: the previous 12 plus CASQ2, DMD, DTNA, FKBP1A, KCNH2, LDB3, LMNA, MIB1, MYH6, NOTCH1, PLN, RYR2, SCN5A, TAZ, and TTN, the latter combination because of the noncompaction phenotype). A change in the amino acid sequence compared with the reference sequence was considered a pathogenic mutation when it met the following criteria: it segregated in the affected family members, it was not present in 200 chromosomes from healthy unrelated individuals, it had not yet been identified in populations of thousands of individuals from different ethnic groups included in the 5000 Genomes Project (Exome Variant Server), the 1000 Genomes Project, or dbSNP (Short Genetic Variations database), and it affected a residue that is phylogenetically conserved between troponin T species and isoforms. An allelic variant was considered rare when segregation could not be demonstrated and the variant was not present in controls, and polymorphic when it was not associated with the disease and it was present in controls. The previously described variants were reviewed to assess their pathogenicity, and new mutations were studied with in silico tools.

Informed consent for DNA extraction was obtained from each individual. The study adhered to the principles of the Declaration of Helsinki, the Council of Europe Convention on Human Rights and Biomedicine, and the UNESCO Universal Declaration on the Human Genome and Human Rights.

Statistical analysis was performed using the SPSS application (v.15.0, SPSS Inc.; Chicago, Illinois, United States). Data with normal distribution are expressed as means (95% confidence interval). The differences between the means were compared using an unpaired 2-tailed Student t test. Categorical data were compared using a chi-square test. Continuous data with abnormal distribution were analyzed with a Mann-Whitney U test. The predefined outcomes for survival analysis were as follows: SCD, first appropriate shock from implantable cardioverter-defibrillator (ICD), death due to heart failure, cardiac transplant, and other cardiovascular death. The cumulative probability for the occurrence of an event was calculated using the Kaplan-Meier method. A comparison was performed with previously published data. Survival analysis from birth was also performed for individual mutations. A probability value of P < .05 was considered statistically significant.


We studied 180 consecutive unrelated probands with cardiomyopathy (15 HCM, 15 DCM, and 10 noncompacted) looking for mutations in the TNNT2 gene and in the 4 other main sarcomere genes (MYBPC3, MHY7, TNNI3, and TPM1); 21 probands (11.7%) had pathogenic mutations in TNNT2. Ninety-eight relatives gave consent for clinical examination (mean, 4.7 relatives/family), and 78 gave consent for genetic analysis of TNNT2; a mutation was found in 33 individuals (42%). The total number of probands plus relatives carrying TNNT2 mutations was 54. Assuming that some first-degree relatives who did not undergo genetic study but who did have HCM had the same TNNT2 mutation, the total was 68 patients: 57 affected individuals and 11 asymptomatic carriers.

In 21 families, 6 different mutations were identified: Arg92Gln in 10 families, Arg286His in 5, Arg278Cys in 3, and Arg92Trp, Arg94His, and Ile221Thr in 1 family each. All these variants except 1 (Ile221Thr) had already been published as causes of HCM.8,14,15,17–19

Double mutations were found in 4 probands (19%): 2 with the Arg278Cys mutation (1 with the Arg502Gln mutation in MYBPC3 and 1 with Arg723Cys in MHY7), 1 proband with the Arg286His mutation and the Arg326Gln mutation in MYBPC3, and 1 proband with the Arg92Gln mutation, who was a carrier of a variant in MYBPC3 that could have acted as a genetic modifier. No relatives were carriers of double mutations. The distribution of mutations and patients was as follows (Figure 1): 30 individuals had Arg92Gln (55.6%), 8 had Arg278Cys (14.8%), 8 had Arg286His (14.8%), 4 had Arg92Trp (7.4%), 3 had Arg94His (5.6%), and 1 had Ile221Thr (1.8%).

Figure 1.

Distribution of mutations and percentage of patients.


All affected patients underwent risk stratification for SCD. Thirteen probands (62%), and 100% of families (n = 10) with the Arg92Gln mutation had a history of SCD.

Electrocardiograms and echocardiograms were studied at the first assessment of all mutation carriers, except for 3 patients (because of SCD being the clinical presentation). The electrocardiograms were generally abnormal (voltage criteria for left ventricular hypertrophy with negative T-waves in precordial and inferior leads), sometimes with only mild abnormalities on echocardiography.

At the first assessment, 9 of the patients with the Arg92Gln mutation had a DCM phenotype with severe left ventricular dysfunction. One affected individual with Arg92Gln had a noncompaction cardiomyopathy phenotype. The others had HCM (Tables 1 and 2).

Table 1.

Clinical and Genetic Data on Patients and Families Included in the Study

Family  TNNT2 mutation  Age/sex  Phenotype  Age at diagnosis, years  FHSD  Presentation  NYHAfunctionnalclass  AF  VT  MMT, mm  LVOT obstruction  LA diameter, mm  LVEF  LGE  PM/ICD (age, years)  Appropriate ICD therapy  Died 
1/Proband  Arg92Gln  22/M  DCM  22  Yes  SCD  No  No  12  No        No    Yes 
1/Mother  Arg92Gln  70/F  DCM  60    Dyspnea  II  Yes  No  11  No  44  40    PM (60)    No 
1/Sister  Arg92Gln  42/F  DCM  42    SCD  Yes  No  No        No    Yes 
2/Proband  Arg92Gln  31/M  HCM  13  Yes  SCD  No  Yes  20  No  48  60    ICD (13)  Yes  No 
2/Father  Arg92Gln  53/M  HCM  37    Family screening  II  Yes  Yes  20  No  52  55    ICD (38)  Yes  No 
2/Aunt  Arg92Gln  45/F  HCM  28    Family screening  III  Yes  No  22  No  50  60  Yes  No    No 
3/Proband  Arg92Gln  64/F  DCM  50  Yes  Dyspnea  II  Yes  No  14  No  50  45  Yes  No    No 
3/Sister  Arg92Gln  40/F  HCM  34    Family screening  No  No  14  No  46  60  Yes  No    No 
3/Grandson*  Arg92Gln  8/M  —      —  No  No  No  25  65    No    No 
3/Brother  Arg92Gln  76/M  DCM  69    Dyspnea  IV  Yes  Yes    No    30    No    Yes 
3/Nephew  Arg92Gln  45/M  HCM  35    Family screening  No  No  17  No  33  48  Yes  No    No 
3/Niece  Arg92Gln  52/F  HCM  43    Family screening  No  No  14  No  45  60    No    No 
3/Grand-nephew  Arg92Gln  21/M  HCM  20    Family screening  No  No  18  No    65  Yes  No    Yes 
3/Grand-niece  Arg92Gln  19/F  HCM  19    Family screening  No  No  14  No    62  Yes  ICD (19)  No  No 
4/Proband  Arg92Gln  72/M  DCM  67  Yes  Dyspnea  III  Yes  No  11  No  55  30  Yes  CRT (69)    Yes 
4/Sister  Arg92Gln  65/F  DCM  55    Dyspnea  III  Yes  Yes  15  No  60  33    ICD (63)  No 
4/Nephew  Arg92Gln  54/M  DCM  50    Dyspnea  III  No  No    No    30    CRT (52)    No 
4/Grand-nephew  Arg92Gln  19/M  HCM  11    SCD  No  Yes  13  No  30  65    ICD (11)  No 
5/Proband  Arg92Gln  66/M  DCM  40  Yes  Chest pain  II  Yes  Yes  20  No  50  30    CRT + ICD (62)  No 
6/Proband  Arg92Gln  49/M  HCM  35  Yes  Family screening  No  Yes  15  No  43  60  Yes  ICD (45)  No  No 
6/Sister  Arg92Gln  54/F  HCM  24    Family screening  II  Yes  Yes  19  No  48  30    ICD  No 
6/Daughter*  Arg92Gln  7/F  —      —  No  No  No  27  70    No    No 
7/Proband  Arg92Gln  40/M  HCM  36  Yes  Family screening  No  No  22  No  47  60  Yes  ICD (38)  No  No 
7/Nephew*  Arg92Gln  12/M  —      —  No  No  No  28  65    No    No 
7/Niece*  Arg92Gln  6/F  —      —  No  No    No    60    No    No 
8/Proband  Arg92Gln  36/M  HCM  17  Yes  SCD  No  Yes  20  No  33  62    ICD (17)  No 
8/Son*  Arg92Gln  8/M  —      —  No  No  No  27  70    No    No 
9/Proband  Arg92Gln  52/F  HCM  51  Yes  Dyspnea  II  No  No  15  No  31  58  No  No    No 
9/Daughter  Arg92Gln  27/F  HCM  26    Family screening  No  No  20  No  29  65  Yes  No    No 
10/Proband  Arg92Gln  46/M  NCCM  40  Yes  Routine ECG  III  No  Yes  10  No  60  21    ICD (44)  No  No 
11/Proband  Arg92Trp  69/F  HCM  57  Yes  Family screening  II  No  No  25  No  42  33    ICD (69)  No  No 
11/Son  Arg92Trp  32/M  HCM  28    Family screening  No  No  15  No  40  65    No    No 
11/Daughter  Arg92Trp  25/F  HCM  20    Family screening  No  No  13  No  40  74  Yes  No    No 
11/Daughter*  Arg92Trp  36/F  —      —  No  No  10  No  33  65    No    No 
12/Proband  Arg278Cys  47/M  HCM  18  No  Routine ECG  No  No  23  No  38  60  Yes  No    No 
12/Father  Arg278Cys  71/M  HCM  57    Routine ECG  No  No  35  Yes  58  58    No    No 
12/Cousin  Arg278Cys  40/M  HCM  37    Family screening  No  No  16  No  36  62    No    No 
13/Proband  Arg278Cys  41/F  HCM  37  No  Dyspnea  No  No  18  No  35  65  Yes  No    No 
13/Brother  Arg278Cys  44/M  HCM  42    Family screening  No  No  22  No  36  70  Yes  No    No 
13/Mother*  Arg278Cys  75/F  —      —  No  No  10  No  32  60    No    No 
14/Proband  Arg278Cys  68/M  HCM  55  No  Chest pain  II  No  Yes  30  No  44  68    ICD (62)  Yes  No 
14/Daughter*  Arg278Cys  29/F  —      —  No  No  No  31  62    No    No 
15/Proband  Arg286His  80/F  HCM  77  Yes  Dyspnea  II  No  No  21  Yes  51  70    PM (79)    No 
15/Son*  Arg286His  48/M  —      —  No  No  10  No  35  65    No    No 
16/Proband  Arg286His  35/M  HCM  25  No  Routine ECG  No  No  21  No  34  60    No    No 
17/Proband  Arg286His  36/F  HCM  34  No  Routine ECG  No  No            No    No 
18/Proband  Arg286His  16/M  HCM  15  No  Routine ECG  No  No  21  No  28  65    No    No 
18/Mother*  Arg286His  40/F  —      —  No  No  10  No  35  60    No    No 
18/Cousin*  Arg286His  6/M  —      —  No  No    No    75    No    No 
19/Proband  Arg286His  53/M  HCM  52  No  Routine ECG  No  No  21  No  32  67  Yes  No    No 
20/Proband  Arg94His  15/M  HCM  14  Yes  Family screening  No  No  33  No  41  64  No  No    No 
20/Father  Arg94His  39/M  HCM  34    Syncope  II  No  No    No    40    ICD (34)  No 
20/Aunt  Arg94His  36/F  HCM  22                      No    Yes 
21/Proband  Ile221Thr  75/F  HCM  62  No  Dyspnea  III  Yes  No  22  Yes  50  60    No    No 

AF, atrial fibrillation; CRT, cardiac resynchronization therapy; DCM, dilated cardiomyopathy; ECG, electrocardiogram; F, female; FHSD, family history of sudden death; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; LA, left atrium; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; M, male; MMT, maximal myocardial thickness; NCCM, noncompaction cardiomyopathy; NYHA, New York Heart Association; PM, pacemaker; SCD, sudden cardiac death; VT, sustained or nonsustained ventricular tachycardia.


Carriers (genotype +, phenotype –).

Table 2.

Clinical, Echocardiographic, and Prognostic Characteristics of Patients with Cardiomyopathy According to the TNNT2 Mutation

  Arg92Gln (n = 25)  Arg278Cys (n = 6)  Arg286His (n = 5)  Arg92Trp (n = 3)  Arg94His (n = 3) 
Age, years  46.4 ± 17  52 ± 14  44 ± 24  42 ± 23  30 ± 13 
Male, No. (%)  14 (56)  5 (83)  3 (60)  1 (33)  2 (66.6) 
Phenotype, No. (%)  HCM, 15 (60); DCM, 9 (36); NCCM, 1 (4)  HCM  HCM  HCM  HCM 
Age at diagnosis, years  37 ± 16  41 ± 14  40.6 ± 24  35 ± 19  23 ± 10 
FHSD, %  100 (n = 21)  0 (n = 3)  20 (n = 5)  100 (n = 1)  0 (n = 1) 
Presentation, %  Family screening, 44; dyspnea, 28; SCD, 20  Family screening, 33; routine ECG, 33; dyspnea, 16; chest pain, 16  Routine ECG, 80; dyspnea, 20  Family screening, 100  Family screening, 33; syncope, 33 
NYHA average  1.76  1.2  1.2  1.3  1.5 
AF, No. (%)  (40) 
VT, No. (%)  (40)  1 (16.6) 
MMT, mm  15.8 ± 4  24 ± 7  21 ± 0  17.7 ± 6   
LVOT obstruction, No. (%)  1 (16.6)  1 (25) 
LA diameter, mm  45 ± 9.6  41 ± 9  36 ± 10  40.6 ± 1.6   
LVEF, %  49 ± 15  64 ± 5  65 ± 4  57 ± 21  52 ± 17 
LGE, No. (%)  10 (91)  3 (100)       
ICD, No. (%)  11 (44)  1 (16.6)  1 (33)  1 (33) 
Died, No. (%)  5 (20)  1 (33) 

AF, atrial fibrillation; DCM, dilated cardiomyopathy; ECG, electrocardiogram; FHSD, family history of sudden death; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; LA, left atrium; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; MMT, maximal myocardial thickness; NCCM, noncompaction cardiomyopathy; NYHA, New York Heart Association; SCD, sudden cardiac death; VT, sustained or nonsustained ventricular tachycardia.

In the analysis of the 57 individuals with cardiomyopathy, the mean age of presentation was 37 ± 17 years; 30 (56%) were male. The initial symptoms were dyspnea in 10 individuals (24%), SCD in 5 (12%), chest pain in 2 (5%), and syncope in 1 (2%); the others were asymptomatic and diagnosis was made following familial screening in 17 (40%) and routine electrocardiography in 7 (17%). Complications during follow-up consisted of ventricular tachycardia or ventricular fibrillation in 3 individuals (7%), heart failure in 17 (40%), syncope in 6 (14%), chest pain in 5 (12%), stroke in 3 (7%), and atrial fibrillation in 11 (24%).

The mean MMT was 18.4 ± 6 (8-35) mm. Patients with the Arg92Gln mutation had a mean MMT of 15.8 ± 4mm. Only 3 (7%) had left ventricular outflow tract obstruction > 30mmHg (1 patient each with the Arg278Cys, Arg286His and Ile221Thr mutations). There was a high prevalence of left ventricular systolic dysfunction, which was present in 12 patients (31%): 10 with the Arg92Gln mutation, 1 with Arg92Trp, and 1 with Arg94His. The mean left atrial diameter was 43 ± 9mm. Cardiac magnetic resonance was performed in 17 patients, 15 of whom (88%) had extensive late gadolinium enhancement.

All patients were followed up (mean, 5 ± 2.5 years). No significant changes were observed in cardiac dimensions or systolic function, independently of cardiac phenotype (HCM, DCM, or noncompaction).

Fourteen individuals (33%) had an ICD implanted: 8 probands (6 as primary prevention and 2 as secondary prevention) and 6 relatives (5 as primary prevention and 1 as secondary prevention). Of 14 patients with ICD, 11 had the Arg92Gln mutation; 1 had Arg92Trp; 1 had Arg278Cys (double mutation in MYBPC3), and 1 had Arg94His.

Three patients with Arg92Gln required a biventricular device for congestive heart failure, and 2 required a dual chamber pacemaker due to sinus dysfunction or atrioventricular block. No patients required myectomy or cardiac transplantation.

During follow-up, 3 patients died: 1 due to heart failure at 60 years (patient with severe left ventricular dysfunction and dilatation, Arg92Gln), another due to stroke (Arg94His), and the third of unknown cause (patient with chronic heart failure and ventricular dysfunction, Arg92Gln phenotype and relatives with Arg92Gln mutation, but no genetic confirmation).

Three patients had at least 1 appropriate ICD shock: 2 with Arg92Gln and 1 with Arg278Cys (this patient had a double mutation in MYBPC3).

Regarding the 11 deaths related to TNNT2 mutations—the total of SCDs from the pedigree analysis (n = 6), SCDs as first presentation of the disease (n = 3), and the deaths during follow-up (n = 2)—6 (54.5%) were related to sport, 9 (81.8%) were male, and the mean age was 21.7 ± 10.9 years. Seven (63.6%) had an HCM phenotype, 2 (18.2%) had a DCM phenotype, and 2 (18.2%) had an unknown phenotype. The mean MMT was 14.6 ± 5mm. Two of the patients who died had had an episode of atrial fibrillation. In the Arg92Gln group, 100% of the group had a family history of SCD vs 28.6% of the group with other TNNT2 mutations distinct from Arg92Gln (P = .008). Sudden cardiac death was the first presentation of disease in 6 patients from the Arg92Gln group; no patients in the group without Arg92Gln had SCD as the first presentation of disease. Also, 3 recoveries from SCD were documented in the group with Arg92Gln and none were documented in the group without. Regarding appropriate ICD therapies, these occurred in 3 patients from the group with Arg92Gln and 1 in the group without. During follow up, 2 patients from the Arg92Gln group died; there were no deaths related to other mutations.

Regarding penetrance, 50% of individuals in the Arg92Gln group had a positive phenotype at 37 years (Figure 2).

Figure 2.

Disease penetrance in carriers of the Arg92Gln mutation: 25% at 23 years, 50% at 37 years, and 75% at 50 years.


Survival from birth was calculated for carriers of TNNT2 mutations, including relatives identified from a family tree who had HCM or were obligate carriers. The Arg92Gln mutation was associated with a higher rate of SCD at a young age. The mean survival of patients with Arg92Gln was 54 years (95% confidence interval, 46-62 years), but decreased to 48 years if patients with recovery from SCD or appropriate ICD shock were included (Figure 3). In the group with Arg92Gln, survival at 55 years was only 50% (95% confidence interval, 41%-58%).

Figure 3.

A: Sudden cardiac death-free survival of all individual carriers of the Arg92Gln mutation (including relatives with hypertrophic cardiomyopathy and obligate carriers). B: As in A, but including recovery from sudden cardiac death and patients with appropriate therapies from implantable cardioverter defibrillator.


The low rate of SCD hampered subgroup analysis. However, when probands were compared with relatives, there was no difference in cardiac mortality (Kaplan-Meier log rank test, P = .62). Survival curves of the study population were compared: the Arg92Gln mutation was compared against the 5 other TNNT2 mutations (due to the different prognostic profile previously mentioned), against other sarcomeric genetic mutations, and against patients with no identified mutation (Figure 4). Analysis of the survival curve showed that patients with the Arg92Gln mutation had a much lower survival rate than other groups (other TNNT2 mutations, other sarcomeric gene mutations, and patients with no identified mutation). There were statistically significant differences from the group with other TNNT2 mutations (log rank test, 11.71; P = .0006). Also, the group of patients with TNNT2 mutation generally had a worse survival rate than the group with other gene mutations or no identified mutations, but this was due to the patients with the Arg92Gln mutation. Patients with double mutations were not analyzed together with other individual mutations.

Figure 4.

A: Sudden cardiac death-free survival in the 4 groups of patients with hypertrophic cardiomyopathy according to genetic result. B: Sudden cardiac death-free survival including recovery from sudden cardiac death and patients with appropriate implantable cardioverter-defibrillator therapies.


Mutations in TNNT2 are considered an infrequent cause of HCM (5%).8,9,20,21 In this study, the prevalence of TNNT2 mutations was higher than in previous series,9,10,17,18,22–24 partly because of a probable founder effect. This study had the highest number of families, and one of the broadest longitudinal cohorts of TNNT mutations (Table 3) since the first published study to show a high incidence of SCD in such patients.9 Our results confirm that SCD is common in young people with some mutations of this gene, but this finding cannot be extrapolated to all known mutations.

Table 3.

Published Studies on Survival With Mutations in the TNNT2 Gene

Study  No. of families  No. of patients  No. of cardiac deaths  No. of sudden deaths  Mutations 
Watkins et al9  11  112  50  39  Ile79AsnArg92GlnPhe110IleΔGlu160Glu163LysGlu244AspIntron 15 G>A Arg278Cys 
Nakajima-Tanaguchi et al22  Ala104Val 
Moolman et al10  22  Arg92Trp 
Anan et al17  18  Phe110Ile 
Torricelli et al18  10  Phe110IleArg130CysΔGlu160Arg92GlnArg278Cys 
Pasquale et al23  20  92  Arg278CysArg92LeuArg92TrpΔGlu163IVS15+1G>AAla104Val Arg278HisArg92Gln Arg94LeuGlu163LysGlu83LysIle79Asn 
Ripoll-Vera et al, 2015*  21  54  11  Arg92GlnArg92TrpArg286HisArg278CysArg94HisIle221Thr 

Current study results.

Electrocardiography was almost always abnormal, sometimes with only mild abnormalities on echocardiography, which underscores the role of both investigations in detecting this disease, something which has previously been expressed, but is important to reiterate.

In comparison with previous studies,9,10,17,18,22–24 there was a lower prevalence of left ventricular outflow tract obstruction at rest, which was present in only 7% of patients, somewhat similar to the most recent published study.23

We identified 6 studies on mutations in TNNT2 that analyzed survival.9,10,17,18,22,23 They comprised a total of 258 carriers and 68 deaths apparently of cardiovascular causes, mostly sudden, but 50 of those deaths were from only 1 publication. Therefore, most of those studies had a low number of SCDs, which coincides with the prospective data from this study (Table 3).

Family tree analysis (Figure 5) showed a high prevalence of SCD in affected families, but only with some mutations (mainly Arg92Gln, but also Arg92Trp and Arg94His). The SCD rate was too small to perform adequate statistical analysis of subgroups, as was the case in previous studies.23 The different prognoses in families with the same mutations indicates that other mechanisms (genetics, epigenetics, or environmental factors) could have had an influence.

Figure 5.

Family trees of the 3-Arg92Gln- (A), 4-Arg92Gln- (B), 11-Arg92Trp- (C) and 12-Arg278Cys- (D) families. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; SCD, sudden cardiac death; SD, sudden death; y, years.


Previous studies24 have already documented cases of SCD with little or even no hypertrophy in carriers of TNNT2 mutations. This was also observed in some of our patients, but only with the Arg92Gln mutation. In patients who had SCD, HCM was more common than DCM, and MMT was only 14.6 ± 6mm. Because of the relative lack of events in the present cohort, the relative risk of SCD could not be determined in mutation carriers who had normal echocardiograms.

This study has detected important prognostic differences between patients with 1 of the TNNT2 mutations (Arg92Gln) and those with the 5 other TNNT2 mutations, other sarcomeric gene mutations, and no identified mutation. Compared with other groups, patients with the Arg92Gln mutation had an earlier presentation and worse prognosis. They had a high incidence of SCD, a mixed phenotype (HCM with mild hypertrophy, DCM with ventricular dysfunction, noncompaction cardiomyopathy), absence of obstruction, significant fibrosis, and frequent need for ICD or resynchronization therapy.

Progressive thinning of the myocardium and deterioration in contractile function are a well-known phenomenon of HCM.3,4 In this study, 9 patients already had ventricular dilatation at presentation (age, 50.6 ± 14.6 years, all with Arg92Gln) and 2 died of heart failure during follow-up, indicating that progression of heart failure could be relatively common in such patients. In fact, the patients with HCM were younger (28.8 ± 11.8 years) than those with DCM. However, there were no cases of progressive ventricular dilatation. This could have been due to the short follow-up, and therefore we cannot conclude with complete certainty that patients with DCM at diagnosis really were patients with HCM in burn-out phase.

One proband with Arg92Gln had noncompaction cardiomyopathy, an association that had not been described until now. It is important to remember that the TNNT2 gene should always be included in genetic study in patients with HCM and DCM, and possibly also, based on our findings, in cases of noncompaction cardiomyopathy.

The Arg92Trp mutation affects the same amino acid as Arg92Gln, and therefore it behaves similarly. It is associated with HCM, mild hypertrophy, and a high incidence of SCD.5,19

The Arg278Cys mutation is also associated with late-presentation HCM and mild-to-moderate hypertophy.9,18,25–27 Sudden cardiac death is uncommon in young people but is common in patients of advanced age. It is often associated with other pathogenic variants.27 From the 3 families with the Arg278Cys mutation, 2 probands had double mutations. There was no history of SCD, and the MMT was highly variable (14-35mm).

The Arg286His mutation has been associated with HCM.19 The 3 families with this mutation had HCM with an MMT of 21mm, without a high risk of SCD.

The Arg94His mutation is also a known cause of HCM. The first symptoms can manifest in childhood and patients may also have severe arrhythmic events with an apparently mild phenotype.28

Finally, the Ile221Thr mutation had not previously been published. It was considered a rare genetic variant affecting 1 relevant functional region. It could only be studied in the index case (with clear HCM), and therefore it was not possible to study its segregation in the family to confirm its pathogenicity.

Double mutations could confer a worse prognosis. Other studies on mutations in the TNNT2 gene did not offer data on additional mutations on other genes. In this series, double mutations were found in 4 probands (19%), but no double mutations were found in the relatives studied. In the literature, double mutations are found in only 5% of cases of HCM.7,23 Only 1 of our 4 patients with a double mutation had an unfavorable risk stratification, and had ICD implantation, but there were insufficient data to establish a prognosis relating to double mutations.

A probable founder effect was demonstrated for the Arg92Gln mutation. Of the 10 families, 9 originated from the same village. Using extensive genealogical study (parish archives and population census), we found that 6 of these families had a common ancestor born in 1784. Haplotype study was not performed as it was not available in our setting.


As with previous studies, there could have been selection bias because the study was carried out in a specialized unit. Patients with genetic and clinical (or pathological) confirmation were included, as were relatives with a positive phenotype and those who had sudden death, who were also presumed to be affected despite not having genetic confirmation.

The phenotypic differences found between some patients with the same mutations shows that the prognosis of these individuals is influenced by many factors other than the mutation itself.


Investigation of the genotype-phenotype correlation in HCM remains a challenge. Mutations in the TNNT2 gene were more common in our series than in previous studies, partly because of a probable founder effect. The clinical and prognostic profiles depended greatly on the mutation. Risk profile was significantly worse in carriers of Arg92Gln than in other patients. Sudden cardiac death was a frequent complication and can occur in young individuals with little or no hypertrophy. Dilated cardiomyopathy with ventricular dysfunction was fairly common among carriers of some mutations (Arg92Gln).

Overall, these findings have important implications for the clinical and genetic study of families with cardiomyopathy, above all the finding of the Arg92Gln mutation, which, given its demonstrated malignancy, should cause a change in the management of individuals in SCD prevention.


Red de Investigación Cardiovascular del Instituto de Salud Carlos III (RD12/004/0069) and CIBEROBN (Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y la Nutrición) (CB12/03/30038), Madrid, Spain.


None declared.

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