Associação entre perfil clínico e genético de adultos com aortopatia: estudo de coorte retrospectivo com seguimento prospectivo
Associação entre perfil clínico e genético de adultos com aortopatia: estudo de coorte retrospectivo com seguimento prospectivo
Data
2022
Autores
Ferreira, Juliana da Rocha
Journal Title
Journal ISSN
Volume Title
Publisher
Instituto Nacional de Cardiologia
Resumo
As aortopatias são uma doença clinicamente silenciosa, com história natural de elevada mortalidade. As doenças da aorta torácica hereditárias (DAT-H) têm sido associadas a mutações em múltiplos genes e estima-se que 30% dos pacientes carreiem uma mutação patogênica. Este estudo teve como objetivo investigar o perfil clínico e genético de adultos portadores de aortopatias e associar genótipo e fenótipo. Foram estudados 79 pacientes com aortopatias, submetidos à análise de dados clínicos e à testagem genética baseada no sequenciamento de nova geração dirigido (tNGS) e pelo método Sanger. As variantes encontradas foram classificadas pelos critérios da American College of Medical Genetics (ACMG). Este estudo definiu uma população fenotípica grave. A dissecção aórtica ocorreu em 49,4% dos pacientes diagnosticados aos 44,59 anos, principalmente a partir dos 40 anos e 72,2% necessitaram de cirurgia. Foram descobertas 7 variantes patogênicas (VP), 4 variantes provavelmente patogênicas (VPP) e 22 variantes de significado incerto. As variantes VP e VPP foram identificadas em 6 genes (ACTA2, FBN1, MYLK, SMAD3, TGFB2, TGFBR2), sendo o FBN1 o mais prevalente (6 variantes). Sete VP/VPP são variantes novas. O rendimento diagnóstico por tNGS foi 10,37% nas DAT isoladas nessa coorte. Já o rendimento diagnóstico dos casos suspeitos de síndrome de Marfan pelo sequenciamento direto do gene da fibrilina-1 (FBN1) foi 37,5%, com 2 VP e 1 VPP. Pacientes com VP/VPP apresentaram média de idade menor ao diagnóstico (39,3 anos) do que sem VP/VPP (44,4 anos) e maior diâmetro médio da aorta (6,56 cm vs. 5,6 cm), diferença sem significado estatístico. Ambos os grupos necessitaram de cirurgia (81,8% vs. 70,6%, respectivamente). Conclui-se que a população estudada apresentou idade diagnóstica precoce e alto percentual de dissecção de aorta. A maioria necessitou de cirúrgica precoce e de emergência/urgência, sendo que a metade nos primeiros meses após o diagnóstico. Síndrome aórtica aguda foi o principal desfecho clínico da população. A associação entre o fenótipo dos pacientes e a análise genética mostrou que o maior rendimento do sequenciamento genético foi encontrado em pacientes mais graves e com idade diagnóstica mais jovem.
Palavras-chave: Aneurisma da aorta torácica; Fibrilina-1; Dissecção aórtica; Testes genéticos; Sequenciamento de nova geração.
Aortopathies are a clinically silent disease, with a natural history of high mortality. Inherited thoracic aortic diseases (HATD) have been associated with mutations in multiple genes and it is estimated that 30% of patients carry a pathogenic mutation. This study aimed to investigate the clinical and genetic profile of adults with aortopathies and to associate genotype and phenotype. A total of 79 patients with aortopathies were studied and subject to clinical data analysis and genetic testing based on directed next-generation sequencing (tNGS) and the Sanger method. The variants found were classified according to the American College of Medical Genetics (ACMG) criteria. This study defined a severe phenotypic population. Aortic dissection occurred in 49.4% of patients diagnosed at 44.59 years of age, mainly after 40 years of age, and 72.2% required surgery. 7 pathogenic variants (VP), 4 probably pathogenic variants (PPV) and 22 variants of uncertain significance were discovered. The VP and VPP variants were identified in 6 genes (ACTA2, FBN1, MYLK, SMAD3, TGFB2, TGFBR2), with FBN1 being the most prevalent (6 variants). Seven VP/VPP are new variants. The diagnostic yield by tNGS was 10.37% in the ATDs isolated in this cohort. The diagnostic yield of suspected cases of Marfan syndrome by direct sequencing of the fibrillin-1 gene (FBN1) was 37.5%, with 2 PV and 1 PPV. Patients with PV/PPV had a lower mean age at diagnosis (39.3 years) than those without PV/PPV (44.4 years) and a greater mean aortic diameter (6.56 cm vs. 5.6 cm), a difference without statistical significance. Both groups required surgery (81.8% vs. 70.6%, respectively). It is concluded that the population studied had an early diagnostic age and a high percentage of aortic dissection. Most required early and emergency/urgent surgery, half of them in the first months after diagnosis. Acute aortic syndrome was the main clinical outcome of the population. The association between patient phenotype and genetic analysis showed that the highest yield of genetic sequencing was found in more severe patients and with younger diagnostic age. Keywords: Aortic aneurysm, thoracic; Fibrilin-1; Aneurysm, dissecting; Genetic testing; High-throughput nucleotide sequencing.
Aortopathies are a clinically silent disease, with a natural history of high mortality. Inherited thoracic aortic diseases (HATD) have been associated with mutations in multiple genes and it is estimated that 30% of patients carry a pathogenic mutation. This study aimed to investigate the clinical and genetic profile of adults with aortopathies and to associate genotype and phenotype. A total of 79 patients with aortopathies were studied and subject to clinical data analysis and genetic testing based on directed next-generation sequencing (tNGS) and the Sanger method. The variants found were classified according to the American College of Medical Genetics (ACMG) criteria. This study defined a severe phenotypic population. Aortic dissection occurred in 49.4% of patients diagnosed at 44.59 years of age, mainly after 40 years of age, and 72.2% required surgery. 7 pathogenic variants (VP), 4 probably pathogenic variants (PPV) and 22 variants of uncertain significance were discovered. The VP and VPP variants were identified in 6 genes (ACTA2, FBN1, MYLK, SMAD3, TGFB2, TGFBR2), with FBN1 being the most prevalent (6 variants). Seven VP/VPP are new variants. The diagnostic yield by tNGS was 10.37% in the ATDs isolated in this cohort. The diagnostic yield of suspected cases of Marfan syndrome by direct sequencing of the fibrillin-1 gene (FBN1) was 37.5%, with 2 PV and 1 PPV. Patients with PV/PPV had a lower mean age at diagnosis (39.3 years) than those without PV/PPV (44.4 years) and a greater mean aortic diameter (6.56 cm vs. 5.6 cm), a difference without statistical significance. Both groups required surgery (81.8% vs. 70.6%, respectively). It is concluded that the population studied had an early diagnostic age and a high percentage of aortic dissection. Most required early and emergency/urgent surgery, half of them in the first months after diagnosis. Acute aortic syndrome was the main clinical outcome of the population. The association between patient phenotype and genetic analysis showed that the highest yield of genetic sequencing was found in more severe patients and with younger diagnostic age. Keywords: Aortic aneurysm, thoracic; Fibrilin-1; Aneurysm, dissecting; Genetic testing; High-throughput nucleotide sequencing.
Description
Palavras-chave
Aneurisma da aorta torácica, Fibrilina-1, Dissecção aórtica, Testes genéticos, Sequenciamento de nova geração, Aortic aneurysm, thoracic, Fibrilin-1, Aneurysm, dissecting, Genetic testing, High-throughput nucleotide sequencing
Citação
Ferreira JR. Associação entre perfil clínico e genético de adultos com aortopatia: estudo de coorte retrospectivo com seguimento prospectivo. Dissertação [Mestrado Profissional em Ciências Cardiovasculares]. Instituto Nacional de Cardiologia; 2022.