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INTRODUCTION AND OBJECTIVES: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. METHODS: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. RESULTS: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). CONCLUSIONS: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.
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Amiloidosis/patología , Cardiomiopatías/patología , Diagnóstico Tardío/estadística & datos numéricos , Insuficiencia Cardíaca/etiología , Derivación y Consulta/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/patología , Cardiomiopatías/diagnóstico , Cardiomiopatías/epidemiología , Cardiomiopatías/terapia , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Miocardio , PrealbúminaRESUMEN
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy type V (ARVC-5) is the most aggressive heterozygous form of ARVC. It is predominantly caused by a fully penetrant mutation (p.S358L) in the nondesmosomal gene TMEM43-endemic to Newfoundland, Canada. To date, all familial cases reported worldwide share a common ancestral haplotype. It is unknown whether the p.S358L mutation by itself causes ARVC-5 or whether the disease is influenced by genetic or environmental factors. OBJECTIVE: The purpose of this study was to examine the phenotype, clinical course, and the impact of exercise on patients with p.S358L ARVC-5 without the Newfoundland genetic background. METHODS: We studied 62 affected individuals and 73 noncarriers from 3 TMEM43-p.S358L Spanish families. The impact of physical activity on the phenotype was also evaluated. RESULTS: Haplotype analysis revealed that the 3 Spanish families were unrelated to patients with ARVC-5 with the Newfoundland genetic background. Two families shared 10 microsatellite markers in a 4.9 cM region surrounding TMEM43; the third family had a distinct haplotype. The affected individuals showed a 38.7% incidence of sudden cardiac death, which was higher in men. Left ventricular involvement was common, with 40% of mutation carriers showing a left ventricular ejection fraction of <50%. Compared with noncarriers, the R-wave voltage in lead V3 was lower (3.2 ± 2.8 mV vs 7.5 ± 3.6 mV; P < .001) and QRS complex in right precordial leads wider (104.7 ± 24.0 ms vs 88.2 ± 7.7 ms; P = .001). A history of vigorous exercise showed a trend toward more ventricular arrhythmias only in women (P = .053). CONCLUSION: ARVC-5 is associated with a high risk of sudden cardiac death and characteristic clinical and electrocardiographic features irrespective of geographical origin and genetic background. Our data suggest that, as in desmosomal ARVC, vigorous physical activity could aggravate the phenotype of TMEM43 mutation carriers.
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Displasia Ventricular Derecha Arritmogénica/genética , ADN/genética , Electrocardiografía , Proteínas de la Membrana/genética , Mutación Missense , Volumen Sistólico/fisiología , Función Ventricular Izquierda/fisiología , Adulto , Displasia Ventricular Derecha Arritmogénica/metabolismo , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Linaje , FenotipoAsunto(s)
Cardiomiopatía Restrictiva , Adulto , Miosinas Cardíacas/genética , Cardiomiopatía Restrictiva/diagnóstico , Cardiomiopatía Restrictiva/genética , Proteínas Portadoras/genética , Femenino , Filaminas/genética , Pruebas de Función Cardíaca/métodos , Humanos , Masculino , Persona de Mediana Edad , Cadenas Pesadas de Miosina/genética , Gravedad del Paciente , Análisis de Secuencia de ADN/métodosRESUMEN
AIMS: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes. Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF. METHODS AND RESULTS: We prospectively screened all consecutive patients ≥60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction ≥50%] with LV hypertrophy (≥12 mm). All eligible patients were offered a (99m)Tc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82 ± 8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2-19.5) showed a moderate-to-severe uptake on the (99m)Tc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutations were found. An endomyocardial biopsy was performed in four patients, confirming ATTRwt in all cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P = 0.019), median troponin I (0.135 vs. 0.025 µg/L; P < 0.001), mean LV maximal wall thickness (17 ± 3.4 vs. 14 ± 2.5 mm; P = 0.001), rate of pericardial effusion (44 vs. 19%; P = 0.047), and rate of pacemakers (44 vs. 12%; P = 0.004), clinical overlap between ATTRwt and other HFpEF forms was high. CONCLUSION: ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients.
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Neuropatías Amiloides Familiares/complicaciones , Insuficiencia Cardíaca/etiología , Anciano , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/fisiopatología , Estudios Transversales , Difosfonatos , Ecocardiografía , Electrocardiografía , Femenino , Genotipo , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Tiempo de Internación , Masculino , Persona de Mediana Edad , Compuestos de Organotecnecio , Estudios Prospectivos , Cintigrafía , Radiofármacos , Volumen Sistólico/fisiologíaRESUMEN
Polymerase γ (POLG) is the enzyme responsible for the replication and maintenance of mitochondrial DNA (mtDNA). Mutations in the POLG1 gene can lead to mitochondrial dysfunction, producing a wide range of neurological and non-neurological phenotypes. Neurological manifestations include ataxia, muscular weakness, epilepsy, progressive external ophthalmoplegia (PEO), ptosis, neuropathy, psychiatric disorders and, more rarely, parkinsonism. We present the case of an 80-year old female patient with a history of PEO, ptosis, childish behaviour, obsessive disorder, cognitive decline, and parkinsonism. A comprehensive study showed striatal dopamine deficiency on DaT Scan and ragged red fibres as evidenced by Gomori staining in a biopsy of the biceps brachii. Multiple deletions of mtDNA were detected, and sequencing of the POLG1 gene identified a novel substitution, 2834A>T, in exon 18, changing the p.His945Leu amino acid. In silico analysis using PolyPhen-2 (http://genetics.bwh.hardvard.edu/pph2/) predicted that this change is probably damaging, with a score of 1.0 (0-1).
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Trastornos del Conocimiento/genética , ADN Polimerasa Dirigida por ADN/genética , Trastornos Mentales/genética , Mutación/genética , Trastornos Parkinsonianos/genética , Anciano de 80 o más Años , Trastornos del Conocimiento/diagnóstico , ADN Polimerasa gamma , ADN Mitocondrial/genética , Femenino , Humanos , Trastornos Mentales/diagnóstico , Trastornos Parkinsonianos/diagnósticoAsunto(s)
Proteínas de Transporte de Catión/genética , Ferritinas/sangre , Hemocromatosis/genética , Algoritmos , Proteínas de Transporte de Catión/deficiencia , Análisis Mutacional de ADN , Femenino , Genotipo , Hemocromatosis/diagnóstico , Humanos , Hierro/sangre , Hígado/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , España , Transferrina/análisisAsunto(s)
Cardiomiopatías/genética , ADN Mitocondrial/genética , Mitocondrias Cardíacas/genética , Enfermedades Mitocondriales/genética , Mutación , Biopsia , Cardiomiopatías/diagnóstico , Cardiomiopatías/metabolismo , Análisis Mutacional de ADN , Ecocardiografía , Electrocardiografía , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/metabolismo , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
BACKGROUND: Mitochondrial DNA maintenance disorders are an important cause of hereditary ataxia syndrome, and the majority are associated with mutations in the gene encoding the catalytic subunit of the mitochondrial DNA polymerase (DNA polymerase gamma), POLG. Mutations resulting in the amino acid substitutions A467T and W748S are the most common genetic causes of inherited cerebellar ataxia in Europe. METHODS: We report here a POLG mutational screening in a family with a mitochondrial ataxia phenotype. To evaluate the likely pathogenicity of each of the identified changes, a 3D structural analysis of the PolG protein was carried out, using the Alpers mutation clustering tool reported previously. RESULTS: Three novel nucleotide changes and the p.Q1236H polymorphism have been identified in the affected members of the pedigree. Computational analysis suggests that the p.K601E mutation is likely the major contributing factor to the pathogenic phenotype. CONCLUSIONS: Computational analysis of the PolG protein suggests that the p.K601E mutation is likely the most significant contributing factor to a pathogenic phenotype. However, the co-occurrence of multiple POLG alleles may be necessary in the development an adult-onset mitochondrial ataxia phenotype.
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Ataxia Cerebelosa/genética , ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Mitocondrias/genética , Mutación , Fenotipo , Anciano , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Secuencia de Bases , Ataxia Cerebelosa/fisiopatología , ADN Polimerasa gamma , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/patología , Modelos Moleculares , Datos de Secuencia Molecular , LinajeRESUMEN
Confirming the pathogenicity of mitochondrial tRNA point mutations is one of the classical challenges in the field of mitochondrial medicine. In addition to genetic and functional studies, the evaluation of a genetic change using a pathogenicity scoring system is extremely useful to discriminate between disease-causing mutations from neutral polymorphisms. The pathogenicity scoring system is very robust for confirming pathogenicity, especially of mutations that show impaired activity in functional studies. However, mutations giving normal results using the same functional approaches are disregarded, and this compromises the power of the system to rule out pathogenicity. We propose to include a new criterion in the pathogenicity scoring systems regarding mutations which fail to show any mitochondrial defect in functional studies. To evaluate this proposal we characterized two mutations, m.8296A>G and m.8347A>G, in the mitochondrial tRNA(L) (ys) gene (MT-TK) using trans-mitochondrial cybrid analysis. m.8347A>G mutation severely impairs oxidative phosphorylation, suggesting that it is highly pathogenic. By contrast, the behavior of cybrids homoplasmic for the m.8296A>G mutation is similar to cybrids containing wild-type mitochondrial DNA (mtDNA). The results indicate that including not only positive but also negative outcomes of functional studies in the scoring system is critical for facilitating the diagnosis of this complex group of diseases.
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Esclerosis Cerebral Difusa de Schilder/diagnóstico , Adolescente , Edad de Inicio , Encéfalo/patología , ADN Polimerasa gamma , ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Esclerosis Cerebral Difusa de Schilder/epidemiología , Esclerosis Cerebral Difusa de Schilder/genética , Esclerosis Cerebral Difusa de Schilder/patología , Progresión de la Enfermedad , Electromiografía , Epilepsias Parciales/genética , Heterogeneidad Genética , Homocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patología , Mutación Missense , Fenotipo , Mutación PuntualRESUMEN
BACKGROUND: Mitochondrial disorders (MD) are multisystem diseases that arise as a result of dysfunction of the oxidative phosphorylation system. The predominance of neuromuscular manifestations in MD could mask the presence of other clinical phenotypes such as cardiac dysfunction. Reported here is a retrospective study, the main objective of which was to characterize the clinical and molecular features of a cohort of patients with cardiomyopathy and MD. METHODS AND RESULTS: Hospital charts of 2,520 patients, evaluated for presumed MD were reviewed. The clinical criterion for inclusion in this study was the presence of a cardiac disturbance accompanied by a mitochondrial dysfunction. Only 71 patients met this criterion. The mitochondrial genome (mtDNA) could be sequenced only in 45 and the pathogenicity of 2 of the found changes was investigated using transmitochondrial cybrids. Three nucleotide changes in mtDNA that may be relevant and 3 with confirmed pathogenicity were identified but no mutations were found in the 13 nuclear genes analyzed. CONCLUSIONS: The mtDNA should be sequenced in patients with cardiac dysfunction accompanied by symptoms suggestive of MD; databases should be carefully and periodically screened to discard mitochondrial variants that could be associated with MD; functional assays are necessary to classify mitochondrial variants as pathogenic or polymorphic; and additional efforts must be made in order to identify nuclear genes that can explain some as yet uncharacterized molecular features of mitochondrial cardiomyopathy.
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Cardiomiopatías , Genoma Mitocondrial , Enfermedades Mitocondriales , Polimorfismo Genético , Adolescente , Adulto , Cardiomiopatías/complicaciones , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Estudios RetrospectivosRESUMEN
Discoveries made during the last 20 years have revealed a genetic origin in many cases of dilated cardiomyopathy (DCM). Currently, over 40 genes have been associated with the disease. Mutations in DCM-causing genes induce the condition through a variety of different pathological pathways with complex and not completely understood mechanisms. Genes that encode for sarcomeric, cytoskeletal, nuclear membrane, dystrophin-associated glycoprotein complex and desmosomal proteins are the principal genes involved. In this review we discuss the most frequent DCM-causing genes. We propose a classification in which DCM genes are considered as being major or minor genes according to their mutation frequency and the available supporting evidence. The main phenotypic characteristics associated with each gene are discussed.
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Cardiomiopatía Dilatada/genética , Animales , Calcio/metabolismo , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Proteínas del Citoesqueleto/metabolismo , Metabolismo Energético , Humanos , Contracción MuscularRESUMEN
The mitochondrial DNA m.13513G>A mutation in the ND5 subunit gene is a frequent cause of Leigh syndrome. Patients harboring this mutation typically present with ptosis and cardiac conduction abnormalities, particularly Wolff-Parkinson-White syndrome, and have a late clinical onset, which contrasts with the typical infantile form. The authors describe a patient presenting with intrauterine growth retardation and visual impairment at 3 months of age, followed by infantile spasms, severe gastrointestinal dysmotility, and neurological regression. The patient had hyperlactacidemia and bilateral basal ganglia and brainstem lesions on MRI. Although he did not present cardiac conduction abnormalities, his mother had been diagnosed with Wolff-Parkinson-White syndrome. The m.13513G>A mutation was found in the patient's muscle and in several tissues of his mother. The present results expand the phenotype of Leigh syndrome associated with the m.13513G>A mutation, which should be suspected in patients with early-onset mitochondrial encephalopathy with infantile spasms or prominent gastrointestinal smooth muscle involvement.
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AIMS: Mitochondrial haplogroups are known to influence individual predisposition to a wide spectrum of metabolic and degenerative diseases, including ischaemic cardiovascular diseases. We have examined the influence of the mitochondrial DNA (mtDNA) background on the development of human end-stage heart failure (HF) in patients undergoing heart transplantation. The influence of mtDNA haplogroups on the incidence of transplant-related complications, mainly cardiac allograft vasculopathy (CAV), and on post-transplant survival was also studied. METHODS AND RESULTS: The most common mitochondrial haplogroups in European populations were genotyped in 450 heart transplant recipients, 248 heart transplant donors, and 206 healthy controls. Mitochondrial haplogroups were determined by PCR amplification of short mtDNA fragments, followed by restriction fragment length polymorphism analysis. After adjustment for age and sex the frequency of haplogroup H was significantly higher in heart transplant recipients than in controls [OR: 1.86 (95% confidence intervals, CI: 1.27-2.74), P= 0.014], and in heart donors [OR: 1.47 (95% CI: 0.99-2.19), P= 0.032]. Likewise, haplogroup Uk was found significantly more frequently among CAV patients than in non-CAV heart allograft recipients [OR: 4.1 (95% CI: 1.51-11.42), P= 0.042]. Finally, heart donor haplogroups had no influence on the morbidity or mortality after heart transplantation. CONCLUSIONS: Mitochondrial haplogroups behave like risk factors for the progress to end-stage HF in a Spanish cardiac transplant population. Mitochondrial DNA variants may have some influence on the appearance of cardiac transplant complications.
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ADN Mitocondrial/genética , Haplotipos/genética , Insuficiencia Cardíaca/genética , Trasplante de Corazón , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Femenino , Insuficiencia Cardíaca/cirugía , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Complicaciones Posoperatorias/genética , Estudios Prospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
The aim of this study was to identify the genetic defect in two patients having cardiac dysfunction accompanied by neurological symptoms, and in one case MRI evidence of cortical and cerebellar atrophy with hyperintensities in the basal ganglia. Muscle biopsies from each patient revealed single and combined mitochondrial respiratory chain deficiency. The complete mtDNA sequencing of both patients revealed two transitions in the mitochondrial tRNA(Val) gene (MT-TV) (m.1628C>T in Patient 1, and m.1644G>A in Patient 2). The functional and molecular analyses reported here suggest that the MT-TV gene should be routinely considered in the diagnosis of mitochondrial cardiomyopathies.
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Cardiomiopatías/genética , Enfermedades Mitocondriales/genética , Mutación , ARN de Transferencia de Valina/genética , ARN/genética , Adolescente , Adulto , Análisis Mutacional de ADN , ADN Mitocondrial/química , ADN Mitocondrial/genética , Humanos , Masculino , ARN Mitocondrial , Análisis de Secuencia de ADNRESUMEN
AIMS: Hypertrophic cardiomyopathy (HCM) is characterized by a heterogeneous presentation and clinical course. A minority of HCM patients develop end-stage HCM and require cardiac transplantation. The genetic basis of end-stage HCM is unknown but small series, isolated case reports and animal models have related the most aggressive heart failure course with the presence of multiple mutations. METHODS AND RESULTS: Twenty-six patients (age 40.4 ± 14.5 years; 46% male) transplanted for end-stage HCM underwent genetic screening of 10 HCM-related genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, TNNC1, MYL3, MYL2, ACTC, LDB3). Additional genetic screening of LAMP2/PRKAG2 and mitochondrial DNA (mtDNA) was performed in four and three cases, respectively. Findings were correlated with clinical and histological features. Pathogenic mutations were identified in 15 patients (58%). Thirteen patients (50%) had mutations in sarcomeric genes (six in MYH7, three in MYBPC3, two in MYL2, one in TNNI3, and one in MYL3) and two patients had mutations in LAMP2. Only three patients (13%) had double mutations and all in homozygosis. Except for a more frequent family history of HCM, patients with mutations in sarcomeric genes did not show any clinical feature that distinguished them from patients without mutations in these genes. Evaluation of 44 relatives from 12 families identified 13 mutation carriers, 9 of whom had an overt HCM phenotype. CONCLUSION: Heart transplanted HCM has a heterogeneous genetic background where multiple mutations are uncommon. The clinical course of HCM is not primarily dependent on the presence of multiple sarcomeric mutations. Clinical and genetic evaluation of relatives does not support differential clinical management in HCM based on genetics.
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Cardiomiopatía Hipertrófica/genética , Adulto , Cardiomiopatía Hipertrófica/epidemiología , Cardiomiopatía Hipertrófica/patología , Cardiomiopatía Hipertrófica/cirugía , Femenino , Genotipo , Trasplante de Corazón , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , PrevalenciaRESUMEN
BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) is the most frequent indication for orthotopic heart transplantation. It has been suggested that mutations in genes encoding desmosomal proteins, more typically associated with arrhythmogenic right ventricular cardiomyopathy, are a cause of DCM. OBJECTIVES: To determine the frequency of desmosomal protein gene mutations in heart transplant recipients and their families and to examine histopathological characteristics of explanted organs from mutation carriers. METHODS: 89 unrelated patients aged 47.9±13.5 years (80% male) transplanted for end-stage DCM underwent genetic screening of five desmosomal genes (PKP2, DSP, DSC2, DSG2 and JUP). The findings were correlated with clinical features and histological characteristics in explanted hearts. RESULTS: Pathogenic mutations were identified in 12 patients (13%). Five additional patients (6%) had genetic variants of unknown significance. The clinical phenotype of patients with pathogenic mutations was indistinguishable from that observed in patients without mutations. Evaluation of 76 relatives from 14 families with sequence variants (11 with pathogenic mutations and three with variants of unknown effect) identified 38 mutation carriers, four of whom had an overt DCM phenotype. Evidence of co-segregation of mutations with DCM phenotype was found in five families. Histological evaluation of explanted hearts did not show any specific features in patients with pathogenic mutations. CONCLUSIONS: Mutations in desmosomal genes are frequent in patients with advanced DCM undergoing cardiac transplantation. These findings emphasise the importance of familial evaluation and genetic counselling in patients with end-stage DCM and pose important challenges for current histopathological criteria for arrhythmogenic right ventricular cardiomyopathy.