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1.
Hum Mol Genet ; 33(12): 1090-1104, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38538566

RESUMO

RATIONALE: Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis. OBJECTIVES: Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants. METHODS: A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts. RESULTS: Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0-47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0-54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines. CONCLUSION: Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.


Assuntos
Fibroblastos , Estudos de Associação Genética , Síndrome de Loeys-Dietz , Músculo Liso Vascular , Proteína Smad3 , Humanos , Proteína Smad3/genética , Proteína Smad3/metabolismo , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/patologia , Masculino , Feminino , Fibroblastos/metabolismo , Adulto , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Diferenciação Celular/genética , Linhagem Celular , Miócitos de Músculo Liso/metabolismo , Estudos Retrospectivos , Fenótipo , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Mutação
2.
Eur J Pediatr ; 183(1): 335-344, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37889292

RESUMO

Sudden cardiac arrest (SCA) studies are often population-based, limited to sudden cardiac death, and excluding infants. To guide prevention opportunities, it is essential to be informed of pediatric SCA etiologies. Unfortunately, etiologies frequently remain unresolved. The objectives of this study were to determine paediatric SCA etiology, and to evaluate the extent of post-SCA investigations and to assess the performance of previous cardiac evaluation in detecting conditions predisposing to SCA. In a retrospective cohort (2002-2019), all children 0-18 years with out-of-hospital cardiac arrest (OHCA) referred to Erasmus MC Sophia Children's Hospital or the Amsterdam UMC (tertiary-care university hospitals), with cardiac or unresolved etiologies were eligible for inclusion. SCA etiologies, cardiac and family history and etiologic investigations in unresolved cases were assessed. The etiology of arrest could be determined in 52% of 172 cases. Predominant etiologies in children ≥ 1 year (n = 99) were primary arrhythmogenic disorders (34%), cardiomyopathies (22%) and unresolved (32%). Events in children < 1 year (n = 73) were largely unresolved (70%) or caused by cardiomyopathy (8%), congenital heart anomaly (8%) or myocarditis (7%). Of 83 children with unresolved etiology a family history was performed in 51%, an autopsy in 51% and genetic testing in 15%. Pre-existing cardiac conditions presumably causative for SCA were diagnosed in 9%, and remained unrecognized despite prior evaluation in 13%. CONCLUSION: SCA etiology remained unresolved in 83 of 172 cases (48%) and essential diagnostic investigations were often not performed. Over one-fifth of SCA patients underwent prior cardiac evaluation, which did not lead to recognition of a cardiac condition predisposing to SCA in all of them. The diagnostic post-SCA approach should be improved and the proposed standardized pediatric post-SCA diagnostics protocol may ensure a consistent and systematic evaluation process increasing the diagnostic yield. WHAT IS KNOWN: • Arrests in infants remain unresolved in most cases. In children > 1 year, predominant etiologies are primary arrhythmia disorders, cardiomyopathy and myocarditis. • Studies investigating sudden cardiac arrest are often limited to sudden cardiac death (SCD) in 1 to 40 year old persons, excluding infants and successfully resuscitated children. WHAT IS NEW: • In patients with unresolved SCA events, the diagnostic work up was often incompletely performed. • Over one fifth of victims had prior cardiac evaluation before the arrest, with either a diagnosed cardiac condition (9%) or an unrecognized cardiac condition (13%).


Assuntos
Cardiomiopatias , Cardiopatias , Miocardite , Lactente , Humanos , Criança , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Estudos Retrospectivos , Países Baixos/epidemiologia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Arritmias Cardíacas/complicações , Cardiomiopatias/complicações
3.
Genet Med ; 24(10): 2112-2122, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36053285

RESUMO

PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies. METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire. RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively. CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Actinas/genética , Adulto , Dissecção Aórtica/genética , Aorta , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/genética , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
4.
Echocardiography ; 39(9): 1209-1218, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35978457

RESUMO

BACKGROUND: Genetic testing of relatives of hypertrophic cardiomyopathy (HCM) patients has led to a large group of genotype-positive, phenotype-negative (G+/Ph-) subjects. Prediction of progression to overt HCM in these subjects is challenging. While left atrial (LA) strain is reduced in HCM patients it is currently unknown whether this parameter can be used to predict HCM phenotype progression. METHODS: This study includes 91 G+/Ph- subjects and 115 controls. Standard echocardiographic parameters as well as left ventricular global longitudinal strain (LV GLS) and LA reservoir strain (LASr) were assessed for each patient. Logistic and Cox proportional hazard regression analyses were used to investigate predictors of G+/Ph- status and HCM during follow-up. RESULTS: Independent predictors of G+ status included pathological Q waves (OR 1.60 [1.15-2.23], p < .01), maximal wall thickness (MWT: OR 1.10 [1.07-1.14], p < .001), mitral inflow E wave (OR 1.06 [1.02-1.10, p = .001), A wave (OR 1.06 [1.03-1.10], p < .001), LV GLS (OR .96 [.94-.98], p < .001), and LASr (OR .99 [.97-.99], p = .03). In univariable Cox regression analysis, male sex (HR 2.78 [1.06-7.29], p = .04), MWT (HR 1.72 [1.14-2.57], p = .009) and posterior wall thickness (HR 1.65 [1.17-2.30], p = .004) predicted HCM during a median follow-up of 5.9 [3.2-8.6] years, whereas LASr did not (HR .95 [.89-1.02], p = .14). There were no significant predictors of HCM after multivariable adjustment. CONCLUSION: LASr is significantly impaired in G+/Ph- subjects and is an independent predictor of G+/Ph- status, but did not predict HCM development during follow-up.


Assuntos
Cardiomiopatia Hipertrófica , Sarcômeros , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/genética , Ecocardiografia , Átrios do Coração , Humanos , Masculino , Prognóstico , Sarcômeros/genética , Sarcômeros/patologia
5.
J Med Genet ; 57(1): 23-30, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494578

RESUMO

BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy. METHODS AND RESULTS: Exome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542G>T, p.(Gly181Val), in SOD2. This gene encodes superoxide dismutase 2 (SOD2) or manganese-superoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidation-reduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O2-·) into H2O2. Measurement of hydroethidine oxidation showed a significant increase in O2-· levels in the patient's skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. Lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2. CONCLUSION: Our results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies.


Assuntos
Cardiomiopatia Dilatada/genética , Mutação de Sentido Incorreto , Miocárdio/patologia , Superóxido Dismutase/genética , Sequência de Aminoácidos , Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Dilatada/metabolismo , Sequência Conservada , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Linhagem , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo
6.
Int J Mol Sci ; 23(1)2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-35008861

RESUMO

Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-ß gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options.


Assuntos
Doenças da Aorta/genética , Genômica , Síndrome de Marfan/genética , Adulto , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/patologia , Respiração Celular , Feminino , Fibrilina-1/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Síndrome de Marfan/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
7.
Am Heart J ; 225: 108-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480058

RESUMO

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Heterozigoto , Mutação com Perda de Função , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Proteínas Quinases/genética , Anormalidades Múltiplas/genética , Adulto , Idade de Início , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Ecocardiografia , Eletrocardiografia , Humanos , Lactente , Fenótipo
8.
Cardiology ; 145(7): 413-420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320984

RESUMO

INTRODUCTION: There is limited data on the experience with insertable cardiac monitors (ICMs) in patients with Brugada syndrome. OBJECTIVE: To evaluate the outcome of ICM in symptomatic patients with Brugada syndrome who are at suspected low risk of sudden cardiac death (SCD). METHODS: We conducted a prospective single-center cohort study including all symptomatic patients with Brugada syndrome who received an ICM (Reveal LINQ) between July 2014 and October 2019. The main indication for monitoring was to exclude ventricular arrhythmias as the cause of symptoms and to establish a symptom-rhythm relationship. RESULTS: A total of 20 patients (mean age, 39 ± 12 years; 55% male) received an ICM during the study period. Nine patients (45%) had a history of syncope (presumed nonarrhythmogenic), and 5 patients had a recent syncope (<6 months). During a median follow-up of 32 months (interquartile range, 11-36 months), 3 patients (15%) experienced an episode of nonsustained ventricular arrhythmia. No patient died suddenly or experienced a sustained ventricular arrhythmia, and no patient had a recurrence of syncope. Overall, 17 patients (85%) experienced symptoms during follow-up, of whom 10 patients had an ICM-detected arrhythmia. In 4 patients (20%), the ICM-detected arrhythmia was an actionable event. ICM-guided management included antiarrhythmic drug therapy for symptomatic ectopic beats (n = 3), pulmonary vein isolation, and oral anticoagulation for atrial fibrillation (n = 1), electrophysiological study for risk stratification (n = 1), and pacemaker implantation for atrioventricular block (n = 1). CONCLUSIONS: An ICM can be used to exclude ventricular arrhythmias in symptomatic patients with Brugada syndrome at low risk of SCD. Furthermore, an ICM-detected arrhythmia changed clinical management in 20% of patients.


Assuntos
Bloqueio Atrioventricular/diagnóstico , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/terapia , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Adulto , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Bloqueio Atrioventricular/terapia , Desfibriladores Implantáveis , Eletrocardiografia Ambulatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Adulto Jovem
10.
Hum Mutat ; 39(9): 1173-1192, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29907982

RESUMO

Simultaneous analysis of multiple genes using next-generation sequencing (NGS) technology has become widely available. Copy-number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD)-associated genes. Eight hundred ten patients suspected of H-TAD were analyzed by targeted NGS analysis of 21 H-TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi-)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H-TAD patients.


Assuntos
Aorta Torácica/patologia , Aneurisma da Aorta Torácica/genética , Doenças da Aorta/genética , Variações do Número de Cópias de DNA/genética , Adulto , Aneurisma da Aorta Torácica/patologia , Doenças da Aorta/patologia , Aberrações Cromossômicas , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Exoma/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptor Notch1/genética , Receptores Depuradores Classe F/genética
11.
Hum Mutat ; 39(5): 621-634, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29392890

RESUMO

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-ß (TGF-ß) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-ß signaling. More recently, TGF-ß ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-ß pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-ß signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.


Assuntos
Estudos de Associação Genética , Síndrome de Loeys-Dietz/genética , Mutação/genética , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta3/genética , Animais , Modelos Animais de Doenças , Humanos , Síndrome de Loeys-Dietz/diagnóstico , Camundongos , Transdução de Sinais/genética
13.
Genet Med ; 18(9): 914-23, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26820064

RESUMO

PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.


Assuntos
Cardiopatias Congênitas/genética , Insuficiência Cardíaca/genética , Síndrome do Coração Esquerdo Hipoplásico/genética , Receptor Notch1/genética , Adolescente , Adulto , Idoso , Aorta/fisiopatologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/fisiopatologia , Criança , Pré-Escolar , Feminino , Cardiopatias Congênitas/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem
14.
Am J Hum Genet ; 88(5): 657-63, 2011 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-21549339

RESUMO

The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi.


Assuntos
Mutação , Epilepsias Mioclônicas Progressivas/genética , Proteínas Qb-SNARE/genética , Degenerações Espinocerebelares/genética , Sequência de Aminoácidos , Criança , Consanguinidade , Feminino , Genes Recessivos , Marcadores Genéticos , Complexo de Golgi/genética , Homozigoto , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Epilepsias Mioclônicas Progressivas/patologia , Linhagem , Fenótipo , Proteínas SNARE/genética , Degenerações Espinocerebelares/patologia
15.
Brain ; 136(Pt 4): 1146-54, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23449775

RESUMO

We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.


Assuntos
Mutação , Epilepsias Mioclônicas Progressivas/genética , Epilepsias Mioclônicas Progressivas/fisiopatologia , Fenótipo , Proteínas Qb-SNARE/genética , Adolescente , Adulto , Ataxia/genética , Ataxia/fisiopatologia , Criança , Eletroencefalografia , Europa (Continente) , Feminino , Humanos , Masculino , Mutação/genética , Epilepsias Mioclônicas Progressivas/mortalidade , Mar do Norte , Adulto Jovem
16.
Radiol Cardiothorac Imaging ; 5(2): e230014, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37124643

RESUMO

Left ventricular hypertrophy (LVH) has a broad differential diagnosis. Pathogenic variants of mitochondrial DNA are a rare cause of LVH, and cardiac MRI is a powerful technique that may aid in differentiating such rare causes. This case report presents three siblings with a pathogenic variant of the mitochondrially encoded tRNA isoleucine (MT-TI) gene. A distinctive cardiac phenotype was detected with cardiac MRI. Extensive LVH and dilatation and decreased ejection fraction were observed with a pattern of increased T2 signal and extensive late gadolinium enhancement, which was remarkably consistent among all three siblings. Keywords: Cardiomyopathies, MR Imaging, Hypertrophic Cardiomyopathy, Mitochondrial, Inherited Cardiomyopathy, Left Ventricular Hypertrophy, Cardiovascular MRI, Late Gadolinium Enhancement Supplemental material is available for this article. © RSNA, 2023.

17.
Heart Rhythm ; 20(11): 1512-1521, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37562486

RESUMO

BACKGROUND: Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864_6867dup, p.(Val2290Argfs∗23), was recently identified in Dutch patients with DCM. OBJECTIVES: The report aimed to evaluate the phenotype of FLNC variant carriers and to determine whether this variant is a founder variant. METHODS: Clinical and genetic data were retrospectively collected from variant carriers. Cardiovascular magnetic resonance studies were reassessed. Haplotypes were reconstructed to determine a founder effect. The geographical distribution and age of the variant were determined. RESULTS: Thirty-three individuals (of whom 23 [70%] were female) from 9 families were identified. Sudden cardiac death was the first presentation in a carrier at the age of 28 years. The median age at diagnosis was 41 years (range 19-67 years). The phenotype was heterogeneous. DCM with left ventricular dilation and reduced ejection fraction (<45%) was present in 11 (33%) individuals, 3 (9%) of whom underwent heart transplantation. Cardiovascular magnetic resonance showed late gadolinium enhancement in 13 (65%) of the assessed individuals, primarily in a ringlike distribution. Nonsustained ventricular arrhythmias were detected in 6 (18%), and 5 (15%) individuals received an implantable cardioverter-defibrillator. A shared haplotype spanning 2.1 Mb was found in all haplotyped individuals. The variant originated between 275 and 650 years ago. CONCLUSION: The pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs∗23) is a founder variant originating from the south of the Netherlands. Carriers are susceptible to developing heart failure and ventricular arrhythmias. The cardiac phenotype is characterized by ringlike late gadolinium enhancement, even in individuals without significantly reduced left ventricular function.


Assuntos
Cardiomiopatias , Cardiomiopatia Dilatada , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Variação Biológica da População , Cardiomiopatias/genética , Cardiomiopatia Dilatada/genética , Meios de Contraste , Filaminas/genética , Gadolínio , Estudos Retrospectivos
18.
JCI Insight ; 8(17)2023 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-37561591

RESUMO

Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are incompletely understood, hampering accurate diagnosis and individualized therapy development. Here, we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM. We demonstrated that patient-specific FLII variants, when brought into the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in our patients. Importantly, using these genetic animal models, complemented with in-depth loss-of-function studies, we provided insights into the function of Flii during ventricular chamber morphogenesis in vivo, including myofibril organization and cardiomyocyte cell adhesion, as well as trabeculation. In addition, we identified Flii function to be important for the regulation of Notch and Hippo signaling, crucial pathways associated with cardiac morphogenesis and function. Taken together, our data provide experimental evidence for a role for FLII in the pathogenesis of pediatric CM and report biallelic variants as a genetic cause of pediatric CM.


Assuntos
Cardiomiopatias , Proteínas dos Microfilamentos , Animais , Adesão Celular/genética , Proteínas dos Microfilamentos/genética , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Peixe-Zebra/genética , Transativadores , Cardiomiopatias/genética
19.
Am J Med Genet A ; 158A(11): 2931-4, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22987308

RESUMO

Genome-wide studies may lead to the discovery of genetic variants of potential clinical importance beyond the aims of the study. We performed single nucleotide polymorphism array analysis in a boy with oculocutaneous albinism to identify copy-neutral regions of homozygosity harboring genes involved in melanin biosynthesis. An unanticipated homozygous deletion of chromosome 5p13.3 was discovered, encompassing not only the OCA gene SLC45A2, but also four additional genes. This led to an unexpected presymptomatic diagnosis of alpha-methylacyl-CoA racemase deficiency in the same patient.


Assuntos
Albinismo Oculocutâneo/diagnóstico , Racemases e Epimerases/deficiência , Albinismo Oculocutâneo/genética , Cromossomos Humanos Par 5 , Fácies , Homozigoto , Humanos , Achados Incidentais , Lactente , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Racemases e Epimerases/genética , Deleção de Sequência
20.
Am J Med Genet A ; 158A(10): 2412-20, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22893440

RESUMO

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atypical deletions of chromosome 22q11.2. These deletions comprise the distal part of the common 22q11.2 deleted region but do not encompass the TBX1 gene. Ten similar patients with overlapping distal 22q11.2 deletions have been reported previously. The clinical features of these patients are described and compared to those found in the classic 22q11.2 deletion syndrome. We discuss the possible roles of a position effect or haploinsufficiency of distally located genes (e.g., CRKL) in the molecular pathogenesis of the 22q11.2 deletion syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/patologia , Proteínas com Domínio T/genética , Adolescente , Adulto , Pré-Escolar , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Síndrome de DiGeorge/genética , Feminino , Humanos , Recém-Nascido , Masculino , Fenótipo , Gravidez
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