RESUMO
Formin homology 2 domain-containing 3 (FHOD3) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.
Assuntos
Cardiomiopatia Hipertrófica , Humanos , Cardiomiopatia Hipertrófica/genética , Fenótipo , Homozigoto , Penetrância , Heterozigoto , Forminas/genéticaRESUMO
PURPOSE OF REVIEW: Dilated cardiomyopathy (DCM) is one of the most prevalent primary cardiomyopathies and may be caused by genetic and non-genetic etiologies. DCM may also be the final common pathway of other cardiomyopathies such as hypertrophic, arrhythmogenic, or non-compaction cardiomyopathy. We review the main DCM genetic substrates, specific genotype-phenotype aspects, the role of genetic testing in risk stratification, and advances regarding genotype-based precision medicine. RECENT FINDINGS: Performing a comprehensive genetic study could have a diagnostic yield up to 40% in DCM, and it is considered a cost-effective approach nowadays. The detection of a specific underlying genetic substrate explaining the disease can have important consequences for clinical management, especially for familial cascade screening, optimizing medical treatment, and improving the arrhythmic risk stratification. The identification of the genetic substrate underlying dilated cardiomyopathy makes possible the genotype-phenotype correlation analysis and a better understanding of the natural history of this disease. Nowadays, there are many promising targeting-gene therapies in different developing phases.
Assuntos
Cardiomiopatia Dilatada , Humanos , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/terapia , Testes GenéticosRESUMO
AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Assuntos
Cardiomiopatia Hipertrófica , Proteínas Musculares/genética , Proteínas Quinases/genética , Cardiomiopatia Hipertrófica/genética , Heterozigoto , Humanos , Mutação , SarcômerosRESUMO
Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy (LVH), with wall thickness ≥ 1.5 cm, is a phenotype in search of a diagnosis, which is most often a genetically determined, cardiac exclusive, or systemic disorder. Familial evaluation and genetic testing are required for definitive diagnosis. The role of genetic findings in predicting development of disease, outcomes, and increasingly to guide management is evolving with access to larger data sets. The specific mutation and sex of the patient are important determinants that ultimately are likely to guide management. The genetic/familial evaluation is influenced by the accuracy of the clinical diagnosis and the extent/expertise of the genetic laboratory. Genetic testing in a patient with unexplained LVH without systemic manifestations will yield a definite/likely pathogenetic mutation in a sarcomere (30%-50%), regulatory/functional (10%-15%) or metabolic/syndromic (< 5%) gene associated with Mendelian inheritance. The importance of oligo- and polygenic determinants, usually in the absence of Mendelian inheritance, is under investigation with important implications, particularly related to familial evaluation and definition of risk of disease development in relatives of probands. The results of genetic testing are increasingly important in management strategies related to the use of the implantable cardioverter defibrillator for prevention of sudden death, use of myosin inhibitors for refractory symptoms in patients with and without outflow tract obstruction, and-on the immediate horizon-gene therapy. This review will focus on genetic and outcome data in sarcomeric HCM, and minor causative genes with robust evidence of their association will also be considered.
Assuntos
Cardiomiopatia Hipertrófica , Testes Genéticos , Humanos , Testes Genéticos/métodos , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/terapia , Mutação , Predisposição Genética para Doença , FenótipoRESUMO
BACKGROUND: Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce. OBJECTIVES: This study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort. METHODS: We collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM. RESULTS: Of 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants. CONCLUSIONS: DES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals.
Assuntos
Displasia Arritmogênica Ventricular Direita , Morte Súbita Cardíaca , Desmina , Fenótipo , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Morte Súbita Cardíaca/etiologia , Desmina/genética , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Adulto Jovem , Desfibriladores Implantáveis , Transplante de Coração , AdolescenteRESUMO
BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22â 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124â 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22â 773; 0.004%) and external comparison groups (4/124â 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.
Assuntos
Cardiomiopatia Dilatada , Cardiopatias Congênitas , Masculino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Feminino , Cardiomiopatia Dilatada/patologia , Cardiopatias Congênitas/genética , Arritmias Cardíacas , Fenótipo , Proteínas com Domínio T/genéticaRESUMO
INTRODUCTION AND OBJECTIVES: Missense mutations in the filamin C (FLNC) gene have been reported as cause of inherited cardiomyopathy. Knowledge of the pathogenicity and genotype-phenotype correlation remains scarce. Our aim was to describe a distinctive cardiac phenotype related to rare missense FLNC variants in the ROD2 domain. METHODS: We recruited 21 unrelated families genetically evaluated because of hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM) phenotype carrying rare missense variants in the ROD2 domain of FLNC (FLNC-mRod2). Carriers underwent advanced cardiac imaging and genetic cascade screening. Myocardial tissue from 3 explanted hearts of a missense FLNC carrier was histologically analyzed and compared with an FLNC-truncating variant heart sample and a healthy control. Plasmids independently containing 3 FLNC missense variants were transfected and analyzed using confocal microscopy. RESULTS: Eleven families (52%) with 20 assessed individuals (37 [23.7-52.7]) years showed 15 cases with a cardiac phenotype consisting of an overlap of HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance). During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths) and absence of cardiac conduction disturbances or skeletal myopathy. A total of 6 families had moderate genotype-phenotype segregation, and the remaining were de novo variants. Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology. HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant FLNC. CONCLUSIONS: FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling.
Assuntos
Cardiomiopatias , Cardiomiopatia Hipertrófica , Cardiomiopatia Restritiva , Insuficiência Cardíaca , Humanos , Cardiomiopatia Restritiva/genética , Mutação de Sentido Incorreto , Mutação , Filaminas/genética , Fenótipo , Miocárdio , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genéticaRESUMO
INTRODUCTION AND OBJECTIVES: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.
Assuntos
Cardiomiopatia Hipertrófica , Tropomiosina , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Portugal/epidemiologia , Espanha/epidemiologia , Tropomiosina/genéticaRESUMO
BACKGROUND: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled. OBJECTIVES: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM. METHODS: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR). RESULTS: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene. CONCLUSIONS: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.
Assuntos
Cardiomiopatia Dilatada/genética , Variação Genética , Insuficiência Cardíaca/genética , Adulto , Idoso , Arritmias Cardíacas/fisiopatologia , Feminino , Genótipo , Ventrículos do Coração , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Volume Sistólico/genética , Resultado do Tratamento , Disfunção Ventricular/fisiopatologia , Função Ventricular Esquerda , Remodelação VentricularAssuntos
Displasia Arritmogênica Ventricular Direita , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/terapia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , HumanosRESUMO
Introducción y objetivos Recientemente se han descrito mutaciones missense en la filamina C (FLNC) como causa de miocardiopatía. Los conocimientos sobre la patogenicidad y la correlación genotipo-fenotipo son escasos. Nuestro objetivo es describir un fenotipo cardiaco distintivo relacionado con mutaciones missense en el dominio ROD2 de FLNC (FLNC-mRod2). Métodos Incluimos 21 familias independientes con fenotipo de miocardiopatía hipertrófica (MCH)/miocardiopatía restrictiva (MCR) portadoras de variantes missense en FLNC-mRod2. Se estudió clínicamente a los portadores, además de hacer un cribado en cascada. Se analizó histológicamente el tejido miocárdico de tres corazones explantados y se comparó con un corazón portador de un truncamiento de FLNC y con un control sano. Se transfectaron plásmidos con mutaciones missense de FLNC y se analizaron mediante microscopía confocal. Resultados En 11 familias (52%) con 20 individuos evaluados (37 [23,7-52,7] años), 15 casos presentaron un fenotipo cardiaco consistente en una superposición de MCH-MCR e hipertrabeculación ventricular izquierda (apariencia de dientes de sierra). Durante una mediana de seguimiento de 6,49 años presentaron principalmente insuficiencia cardiaca avanzada (16 (80%) disfunción diastólica, 3 trasplantes cardiacos, 3 muertes por insuficiencia cardiaca) en ausencia de alteraciones de la conducción cardiaca o miopatía esquelética. Un total de 6 familias presentaban segregación genotipo-fenotipo leve, y las restantes eran mutaciones de novo. Se observó una remodelación de la matriz extracelular y distribución de la FLNC diferencial en los cardiomiocitos. Las células HT1080 y H9c2 no revelaron agregados citoplasmáticos de FLNC. Conclusiones Las variantes en FLNC-mRod2 exhiben una alta prevalencia de fenotipo solapado de MCR, MCH e hipertrabeculación en dientes de sierra, con una remodelación histopatológica cardiaca distintiva (AU)
Introduction and objectives Missense mutations in the filamin C (FLNC) gene have been reported as cause of inherited cardiomyopathy. Knowledge of the pathogenicity and genotype-phenotype correlation remains scarce. Our aim was to describe a distinctive cardiac phenotype related to rare missense FLNC variants in the ROD2 domain. Methods We recruited 21 unrelated families genetically evaluated because of hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM) phenotype carrying rare missense variants in the ROD2 domain of FLNC (FLNC-mRod2). Carriers underwent advanced cardiac imaging and genetic cascade screening. Myocardial tissue from 3 explanted hearts of a missense FLNC carrier was histologically analyzed and compared with an FLNC-truncating variant heart sample and a healthy control. Plasmids independently containing 3 FLNC missense variants were transfected and analyzed using confocal microscopy. Results Eleven families (52%) with 20 assessed individuals (37 [23.7-52.7]) years showed 15 cases with a cardiac phenotype consisting of an overlap of HCM-RCM and left ventricular hypertrabeculation (saw-tooth appearance). During a median follow-up of 6.49 years, they presented with advanced heart failure: 16 (80%) diastolic dysfunction, 3 heart transplants, 3 heart failure deaths) and absence of cardiac conduction disturbances or skeletal myopathy. A total of 6 families had moderate genotype-phenotype segregation, and the remaining were de novo variants. Differential extracellular matrix remodeling and FLNC distribution among cardiomyocytes were confirmed on histology. HT1080 and H9c2 cells did not reveal cytoplasmic aggregation of mutant FLNC. Conclusions FLNC-mRod2 variants show a high prevalence of an overlapped phenotype comprising RCM, HCM and deep hypertrabeculation with saw-tooth appearance and distinctive cardiac histopathological remodeling (AU)
Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Restritiva/genética , Mutação/genética , Filaminas/genética , FenótipoRESUMO
El consumo de sustancias tóxicas constituye un factor de riesgo significativo para la muerte súbita cardiaca. Los tóxicos con mayor relevancia son las drogas ilegales (especialmente la cocaína), el alcohol y el tabaco, y en menor medida, las sustancias dopantes. Diversos medicamentos también incrementan el riesgo de muerte súbita cardiaca. En el presente artículo se hace una revisión sobre el mecanismo de acción y la patología inducida por estos tóxicos; se ofrece información epidemiológica, se destaca la trascendencia de una investigación forense protocolizada y se discuten las implicaciones de la patología forense en la prevención. La posibilidad de consumo de drogas de abuso debería ser tenida en cuenta en toda muerte súbita cardiaca de un adolescente, joven o adulto de edad mediana, principalmente en varones. En deportistas sería conveniente descartar el uso de sustancias dopantes; y en pacientes que toman psicofármacos valorar su influencia en el fallecimiento, aún con niveles terapéuticos (AU)
The use of toxic substances is a main risk factor for sudden cardiac death. The most relevant toxic substances are the illegal drugs (especially cocaine), ethanol, tobacco, and doping substances. Additionally, several therapeutic drugs are able to increase the risk for sudden cardiac death. The aim of the present paper is to review the mechanism of action and the main pathological problems induced by toxic substances. Moreover, we provide epidemiological information, underlie the importance of a standardised forensic investigation, and discuss the role of forensic pathology in the prevention of this phenomenon. The possibility of consumption of any drug of abuse should be considered in any case of sudden cardiac death in adolescents, young, or middle-age patients, especially in men. In athletes the use of doping substances should be ruled-out. In patients under psychopharmacological treatment, the putative influence of these drugs should be borne in mind (AU)