Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation

doi:10.1016/j.healun.2015.12.014

The Journal of Heart and Lung Transplantation

Volume 35, Issue 5, May 2016, Pages 625-635

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https://doi.org/10.1016/j.healun.2015.12.014 Get rights and content

Background

Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting.

Methods

Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies.

Results

Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as non-pathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%).

Conclusions

The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases.

Section snippets

Study population

This study was approved by the ethics committee of the participant centers and complied with the Declaration of Helsinki.

A total of 52 non-related patients with HTx due to familial DCM at 3 Spanish heart transplant centers (Hospital Universitario Puerta de Hierro, Hospital Universitario 12 de Octubre and Hospital Universitario Virgen de la Arrixaca) were included in the study.

DCM was defined as familial if 1 or more relative(s) (in addition to the proband) had DCM during life or at post-mortem

Results

The study cohort comprised 52 patients (mean age at first evaluation 39.9 ± 14.3 years, range 11 to 64 years; 92% males). Clinical and familial characteristics are presented in Table S2 in Supplementary material 1 (available online at www.jhltonline.org). Fifty-one patients (98%) had known family history of DCM and 20 (38%) had family history of SCD (7 of those in a relative <35 years of age). Pedigrees of the 52 families are provided (see Supplementary material 2 available online at //www.jhltonline.org

Discussion

In this study we have examined, for the first time, the genetic basis of familial DCM in individuals with HTx. This work is also the first to address the yield of modern NGS technology plus detailed familial studies in this setting. Our findings show that the genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and that several genes are involved in the pathogenesis of the disease. We also found that current NGS genetic studies, when combined with detailed familial

Disclosure statement

I.G.-D. is an employee of Health In Code; L.M. is shareholder of Health In Code; and S.C., L.P.-B., E.L.-P. and P.G.-P. share a patent on diagnostic testing. The other authors have no conflicts of interest to disclose. The authors gratefully acknowledge SecuGen for help with the haplotype analysis and Kenneth McCreath for English editing. This study was supported by the Instituto de Salud Carlos III (Grants PI11/0699, RD012/0042/0015, RD012/0042/0049, RD012/0042/0066 and RD12/0042/0069) and the

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The identified predictors (family history of DCM, absence of hypertension, skeletal muscle disease, absence of LBBB, and low QRS voltage in peripheral ECG leads) were all found to be strong independent predictors of a positive genetic test result. These findings have a biological explanation and are congruent with previous reports demonstrating higher detection rates of P/LP variants in familial DCM (in which a likely genetic etiology must be always suspected),21 skeletal myopathy (considered a strong red flag because of the shared genetic etiology among some forms of genetic DCM and skeletal muscle disease),22 low voltages on ECG (described as a common finding in certain genotypes such as PLN and desmosomal genes),23-26 and absence of LBBB (a potential role of desynchrony itself in LV systolic dysfunction).27 Interestingly, although LBBB and conduction disease are part of the phenotypic expression of certain forms of genetic DCM like LMNA-associated DCM, it was negatively associated with PV/LPVs both in the derivation and the validation cohorts.
Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption.
This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD.
Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries.
A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78).
The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.
Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy
2022, Journal of Heart and Lung Transplantation
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This is comparable to the findings of Cuenca S. et. al who identified a variant in TTN in 10 individuals (19.2%) in a highly selected cohort of HTx patients with familial DCM.30 The role of TTN in DCM might even still be underestimated at this moment since TTN missense variants have not been included so far.
The importance of genetic testing for cardiomyopathies has increased in the last decade. However, in heart transplant patients with former cardiomyopathy, genetic testing in retrospect is not routinely performed. We hypothesize that the yield of genetic testing in this population is considerable, and will have a major impact for both patients and relatives.
Patients that underwent heart transplantation (HTx) between 1995 and 2020 and were still in follow-up, were offered genetic testing if the primary etiology was non-ischemic cardiomyopathy. Next generation sequencing (NGS) of known cardiomyopathy genes was performed and variants were classified as variant of unknown significance (class 3), likely pathogenic (class 4) or pathogenic (class 5) variant.
Of the 99 HTx patients in active follow-up, only 6 patients had a genetic diagnosis at the time of HTx. In this study, 31 selected patients with prior non-ischemic cardiomyopathy underwent genetic testing post HTx. 23/31 patients (74.2%) carried a variant that was classified as class 3 or higher. In 12/31 patients a class 4/5 variant (38.7%) was identified, and in 11/31 patients (35.5%) a class 3 variant. Class 5 Variants in TTN were the most prevalent (7/31), followed by class 5 variants in MYBPC3 (2/31). A positive family history was present in 21/31 (67.7%) and a second precipitating factor (e.g., alcohol abuse, pregnancy) was present in 17/31 patients (54.8%). Diagnostic yield of genetic testing was similar between patients with or without familial history and/or second hit. Through cascade screening 48 family members were screened for presence of a class 4/5 variant, of whom 19 (39.6%) were genotype positive, of whom 10 (52.6%) showed a cardiac phenotype. Appropriate follow-up was offered.
Genetic testing for cardiomyopathy genes established a molecular diagnosis in 38.7% of patients post HTx. These results highlight the importance of genetic testing in this population as it is still often overlooked in patients that already underwent HTx in the past. Genetic testing is highly recommended, independent of family history or second precipitating factors, as it might identify relatives at risk.
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Titin, as the main protein responsible for the passive stiffness of the sarcomere, plays a key role in diastolic function and is a determinant factor in the etiology of heart disease. Titin stiffness depends on unfolding and folding transitions of immunoglobulin-like (Ig) domains of the I-band, and recent studies have shown that oxidative modifications of cryptic cysteines belonging to these Ig domains modulate their mechanical properties in vitro. However, the relevance of this mode of titin mechanical modulation in vivo remains largely unknown. Here, we describe the high evolutionary conservation of titin mechanical cysteines and show that they are remarkably oxidized in murine cardiac tissue. Mass spectrometry analyses indicate a similar landscape of basal oxidation in murine and human myocardium. Monte Carlo simulations illustrate how disulfides and S-thiolations on these cysteines increase the dynamics of the protein at physiological forces, while enabling load- and isoform-dependent regulation of titin stiffness. Our results demonstrate the role of conserved cysteines in the modulation of titin mechanical properties in vivo and point to potential redox-based pathomechanisms in heart disease.
Clinical utility of genetic testing in patients with dilated cardiomyopathy
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La miocardiopatía dilatada (MCD) es la causa más frecuente de trasplante cardiaco. Se considera que es familiar hasta en el 50% de los casos. Nuestro objetivo es describir los resultados genéticos obtenidos en una cohorte de pacientes con MCD, de los cuales una elevada proporción había acabado en trasplante cardiaco.
Se incluyeron pacientes con MCD a los que se realizó next-generation sequencing (NGS, «secuenciación de nueva generación») de al menos 80 genes relacionados con la enfermedad. Se analizaron retrospectivamente los datos clínicos de los pacientes, la historia familiar y los resultados del estudio genético. En los casos en los que fue posible, se realizó una evaluación de sus familiares de primer grado.
Fueron evaluados 87 pacientes con MCD y 308 familiares de 70 familias distintas. La prevalencia clínica de enfermedad familiar fue del 37% (32 pacientes) y el 44% (38 pacientes) habían precisado un trasplante cardiaco. En 43 pacientes (49%) se encontró al menos una variante relevante, en 25 pacientes (29%) se identificaron variantes de significado incierto y en 19 pacientes (22%) el estudio fue negativo. La mayoría de las mutaciones se encontraron en genes sarcoméricos y la rentabilidad del estudio fue mayor en los pacientes con MCD familiar.
El estudio genético NGS en nuestra población de pacientes con MCD tuvo una elevada rentabilidad, alcanzando el 69% en los casos familiares. El espectro mutacional fue heterogéneo y con frecuencia la identificación de la etiología específica de la enfermedad aportó información pronóstica.
Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation. The prevalence of familial disease can reach 50%. Our objective was to describe the genetic basis of DCM in a cohort with a high proportion of transplanted patients.
We included patients with DCM and genetic testing performed using next-generation sequencing (NGS) that included at least 80 genes. Clinical data, family history and genetic results were retrospectively analysed. When possible, assessment of first-degree relatives was carried out.
Eighty-seven DCM patients and 308 relatives from 70 families were evaluated. Clinical prevalence of familial disease was 37% (32 patients). Forty-four percent of patients (38 patients) had required heart transplantation. A relevant variant was found in 43 patients (49%), 25 patients (29%) carried variants of unknown significance and in 19 patients (22%) the study was negative. Most genetic variants were found in sarcomeric genes and the yield of genetic testing was higher in patients with familial DCM.
The yield of genetic testing in our DCM cohort was high, reaching 69% in familial cases. Mutational spectrum was heterogeneous and the identification of the specific aetiology of the disease often provided prognostic information.

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Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation

Background

Methods

Results

Conclusions

Section snippets

Study population

Results

Discussion

Disclosure statement

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Am Coll Cardiol

J Am Coll Cardiol

J Mol Diagn

J Card Fail

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

Eur Heart J

The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy

N Engl J Med

Dilated cardiomyopathy: the complexity of a diverse genetic architecture

Nat Rev Cardiol

Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy

Heart