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1.
Am J Med Genet A ; 188(8): 2389-2396, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35567597

RESUMO

Pathogenic variants in ACTA2, encoding smooth muscle α-actin, predispose to thoracic aortic aneurysms and dissections. ACTA2 variants altering arginine 179 predispose to a more severe, multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM 613834). Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early-onset thoracic aortic disease (TAD), moyamoya-like cerebrovascular disease, and primary pulmonary hypertension. Patients also have dysfunction of other smooth muscle-dependent systems, including congenital mydriasis, hypotonic bladder, and gut hypoperistalsis. Here, we describe five patients with novel heterozygous ACTA2 missense variants, p.Arg179Gly, p.Met46Arg, p.Thr204Ile, p.Arg39Cys, and p.Ile66Asn, who have clinical complications that align or overlap with SMDS. Patients with the ACTA2 p.Arg179Gly and p.Thr204Ile variants display classic features of SMDS. The patient with the ACTA2 p.Met46Arg variant exhibits exclusively vascular complications of SMDS, including early-onset TAD, PDA, and moyamoya-like cerebrovascular disease. The patient with the ACTA2 p.Ile66Asn variant has an unusual vascular complication, a large fusiform internal carotid artery aneurysm. The patient with the ACTA2 p.Arg39Cys variant has pulmonary, gastrointestinal, and genitourinary complications of SMDS but no vascular manifestations. Identifying pathogenic ACTA2 variants associated with features of SMDS is critical for aggressive surveillance and management of vascular and nonvascular complications and delineating the molecular pathogenesis of SMDS.


Assuntos
Actinas , Aneurisma da Aorta Torácica , Transtornos Cerebrovasculares , Permeabilidade do Canal Arterial , Doença de Moyamoya , Actinas/genética , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/genética , Permeabilidade do Canal Arterial/genética , Heterozigoto , Humanos , Doença de Moyamoya/genética , Músculo Liso , Mutação , Fenótipo
2.
Vasc Med ; 25(1): 63-77, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32000633

RESUMO

Aortic aneurysms were the primary cause of nearly 10,000 deaths in 2014 according to data from the Centers for Disease Control and may involve segments of the thoracic or abdominal aorta. Thoracic aortic aneurysms and dissections are more commonly associated with an underlying genetic etiology. In the past several decades, in parallel with the burst of new genome sequencing technologies, a number of genetic aortopathies have been identified. These have provided important insights into the molecular mechanisms of aneurysmal disease, but pose challenges in clinical practice as there are limited consensus recommendations at this time. In this review, we aim to address the pathophysiology, clinical presentation, and treatment considerations in the key heritable thoracic aortopathies.


Assuntos
Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/terapia , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/terapia , Técnicas de Diagnóstico Molecular , Dissecção Aórtica/genética , Aneurisma Aórtico/genética , Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Humanos , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento
3.
J Med Genet ; 56(4): 252-260, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30661052

RESUMO

BACKGROUND: Pathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants. METHODS: Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain. RESULTS: Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed. CONCLUSIONS: SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.


Assuntos
Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Proteína Smad3/genética , Adolescente , Adulto , Idoso , Alelos , Substituição de Aminoácidos , Aneurisma da Aorta Torácica/complicações , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Domínios Proteicos/genética , Fatores de Risco , Proteína Smad3/química
4.
BMC Med Genomics ; 14(1): 66, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648514

RESUMO

BACKGROUND: Disclosure of pathogenic variants to thoracic aortic dissection biobank participants was implemented. The impact and costs, including confirmatory genetic testing in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, were evaluated. METHODS: We exome sequenced 240 cases with thoracic aortic dissection and 258 controls, then examined 11 aortopathy genes. Pathogenic variants in 6 aortopathy genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 participants, representing 10.8% of the cohort (26/240). A second research sample was used to validate the initial findings. Mailed letters to participants disclosed that a potentially disease causing DNA alteration had been identified (neither the gene nor variant was disclosed). Participants were offered clinical genetic counseling and confirmatory genetic testing in a CLIA laboratory. RESULTS: Excluding 6 participants who were deceased or lost to follow-up, 20 participants received the disclosure letter, 10 of whom proceeded with genetic counseling, confirmatory genetic testing, and enrolled in a survey study. Participants reported satisfaction with the letter (4.2 ± 0.7) and genetic counseling (4.4 ± 0.4; [out of 5, respectively]). The psychosocial impact was characterized by low decisional regret (11.5 ± 11.6) and distress (16.0 ± 4.2, [out of 100, respectively]). The average cost for 26 participants was $400, including validation and sending letters. The average cost for those who received genetic counseling and CLIA laboratory confirmation was $605. CONCLUSIONS: Participants were satisfied with the return of clinically significant biobank genetic results and CLIA laboratory testing; however, the process required significant time and resources. These findings illustrate the trade-offs involved for researchers considering returning research genetic results.


Assuntos
Bancos de Espécimes Biológicos , Dissecção Aórtica , Revelação , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade
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