RESUMO
BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes. OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene. METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment. RESULTS: Significant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-ß pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2;P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. CONCLUSIONS: Gene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Dissecção Aórtica/genética , Aneurisma da Aorta Torácica/genética , Criança , Humanos , Mutação , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Estudos RetrospectivosRESUMO
Spontaneous coronary artery dissection (SCAD) is a potential precipitant of myocardial infarction and sudden death for which the etiology is poorly understood. Mendelian vascular and connective tissue disorders underlying thoracic aortic disease (TAD), have been reported in ~5% of individuals with SCAD. We therefore hypothesized that patients with TAD are at elevated risk for SCAD. We queried registries enrolling patients with TAD to define the incidence of SCAD. Of 7568 individuals enrolled, 11 (0.15%) were found to have SCAD. Of the sequenced cases (9/11), pathogenic variants were identified (N = 9), including COL3A1 (N = 3), FBN1 (N = 2), TGFBR2 (N = 2), TGFBR1 (N = 1), and PRKG1 (N = 1). Individuals with SCAD had an increased frequency of iliac artery dissection (25.0% vs. 5.1%, p = 0.047). The prevalence of SCAD among individuals with TAD is low. The identification of pathogenic variants in genes previously described in individuals with SCAD, particularly those underlying vascular Ehlers-Danlos, Marfan syndrome, and Loeys-Dietz syndrome, is consistent with prior reports from clinical SCAD series. Further research is needed to identify specific genetic influences on SCAD risk.
Assuntos
Anomalias dos Vasos Coronários , Síndrome de Ehlers-Danlos , Síndrome de Loeys-Dietz , Doenças Vasculares , Anomalias dos Vasos Coronários/epidemiologia , Anomalias dos Vasos Coronários/genética , Síndrome de Ehlers-Danlos/genética , Predisposição Genética para Doença , Humanos , Síndrome de Loeys-Dietz/complicações , Síndrome de Loeys-Dietz/epidemiologia , Síndrome de Loeys-Dietz/genética , Fatores de Risco , Doenças Vasculares/congênito , Doenças Vasculares/epidemiologia , Doenças Vasculares/genéticaRESUMO
OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.
Assuntos
Colágeno Tipo III/genética , Análise Mutacional de DNA , Síndrome de Ehlers-Danlos/diagnóstico , Mutação , Adolescente , Adulto , Estudos Transversais , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/genética , Feminino , Predisposição Genética para Doença , Alemanha , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estados Unidos , Adulto JovemRESUMO
PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. METHODS: Exome sequencing from 39 trios were analyzed. RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
Assuntos
Transtornos Cerebrovasculares/genética , Doença de Moyamoya/genética , Adulto , Proteínas de Ciclo Celular/genética , Transtornos Cerebrovasculares/metabolismo , Criança , Pré-Escolar , DNA Helicases/genética , Deficiências do Desenvolvimento/genética , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Deficiência Intelectual/genética , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Pessoa de Meia-Idade , Mutação/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sequenciamento do Exoma/métodosRESUMO
OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder owing to pathogenic variants in COL3A1 that lead to impaired type III collagen production. We aim to describe the contemporary multi-institutional experience of aortic and arterial pathology in individuals with vEDS, to evaluate disease patterns and refine management recommendations. METHODS: This cross-sectional, retrospective study of individuals with genetically confirmed vEDS was conducted between 2000 and 2015 at multiple institutions participating in the Vascular Low Frequency Disease Consortium. Aortic and arterial events including aneurysms, pseudoaneurysms, dissections, fistulae, or ruptures were studied. Demographics, COL3A1 variants, management, and outcomes data were collected and analyzed. Individuals with and without arterial events were compared. RESULTS: Eleven institutions identified 86 individuals with pathogenic variants in COL3A1 (47.7% male, 86% Caucasian; median age, 41 years; interquartile range [IQR], 31.0-49.5 years; 65.1% missense COL3A1 variants). The median follow-up from the time of vEDS diagnosis was 7.5 years (IQR, 3.5-12.0 years). A total of 139 aortic/arterial pathologies were diagnosed in 53 individuals (61.6%; 50.9% male; 88.5% Caucasian; median age, 33 years; IQR, 25.0-42.3 years). The aortic/arterial events presented as an emergency in 52 cases (37.4%). The most commonly affected arteries were the mesenteric arteries (31.7%), followed by cerebrovascular (16.5%), iliac (16.5%), and renal arteries (12.2%). The most common management was medical management. When undertaken, the predominant endovascular interventions were arterial embolization of medium sized arteries (13.4%), followed by stenting (2.5%). Aortic pathology was noted in 17 individuals (32%; 58.8% male; 94.1% Caucasian; median age, 38.5 years; IQR, 30.8-44.7 years). Most notably, four individuals underwent successful abdominal aortic aneurysm repair with excellent results on follow-up. Individuals with missense mutations, in which glycine was substituted with a large amino acid, had an earlier onset of aortic/arterial pathology (median age, 30 years; IQR, 23.5-37 years) compared with the other pathogenic COL3A1 variants (median age, 36 years; IQR, 29.5-44.8 years; P = .065). There were 12 deaths (22.6%) at a median age of 36 years (IQR, 28-51 years). CONCLUSIONS: Most of the vEDS arterial manifestations were managed medically in this cohort. When intervention is required for an enlarging aneurysm or rupture, embolization, and less frequently stenting, seem to be well-tolerated. Open repair of abdominal aortic aneurysm seems to be as well-tolerated as in those without vEDS; vEDS should not be a deterrent to offering an operation. Future work to elucidate the role of surgical interventions and refine management recommendations in the context of patient centered outcomes is warranted.
Assuntos
Aneurisma/epidemiologia , Aorta/patologia , Artérias/patologia , Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma/genética , Aneurisma/patologia , Aneurisma/terapia , Aorta/cirurgia , Artérias/cirurgia , Criança , Pré-Escolar , Colágeno Tipo III/metabolismo , Estudos Transversais , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patologia , Embolização Terapêutica/estatística & dados numéricos , Procedimentos Endovasculares/métodos , Procedimentos Endovasculares/estatística & dados numéricos , Feminino , Seguimentos , Testes Genéticos/estatística & dados numéricos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: The c.530G>A (p.Arg177Gln) mutation in PRKG1 has been shown to be associated with thoracic aortic aneurysms and dissections. This rare mutation accounts for an estimated 1% of nonsyndromic heritable thoracic aortic disease. We sought to describe the clinical presentation of type B aortic dissection (TBAD), management, and outcomes in patients with this mutation. METHODS: This is a descriptive multi-institutional retrospective study of patients from six families with the PRKG1 mutation. Patients with TBAD were selected for analysis. Demographics, family histories, TBAD management, and outcomes were reviewed. RESULTS: Of the 29 individuals diagnosed with the PRKG1 mutation, 12 (41.3%) had TBAD (50% male, TBAD median age: 31 years [range, 16-58 years], median follow-up: 6 years [range, 3-15 years] after TBAD). All had a family history of aortic dissections and none had features of Marfan syndrome. The median size of the descending thoracic aorta (DTA) at TBAD was 4.1 cm (range, 3.8-5 cm). Most cases (9 acute TBAD, 1 incidental TBAD diagnosis during screening) were managed medically. One case had open DTA repair the acute phase. Repair for dissection-related aneurysmal degeneration was performed in seven cases (58.3%) in the chronic phase at a median of 2 years (range, 1-8 years) after TBAD. In four cases (33.3%), the DTA remained stable in size over a range of 1 to 7 years after TBAD. Type A aortic dissection subsequent to TBAD occurred in three cases (25%). There were four (33.3%) deaths in the series, all aortic related at a median age of 24 years (range, 19-43 years). CONCLUSIONS: The PRKG1 (p.Arg177Gln) mutation although rare is associated with nonsyndromic TBAD in young and middle-aged patients. Workup for this gene mutation should be included as part of the workup for TBAD etiology in relatively young patients and those with familial history of aortic dissections. Once diagnosed, testing of first-degree family members is warranted. In all individuals with a PRKG1 mutation, close follow-up for aortic root dilatation and hypertension control is essential to reduce the risk of type A or type B aortic dissection, and in cases of TBAD, to decrease the risk of dissection-related aneurysmal degeneration.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Mutação , Adolescente , Adulto , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/enzimologia , Dissecção Aórtica/terapia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/enzimologia , Aneurisma da Aorta Torácica/terapia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Estados Unidos , Adulto JovemRESUMO
SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. At the same time, SMAD4 pathogenic variants have not been reported in thoracic aortic disease families without JPS-HHT. A SMAD4 heterozygous variant, c.290G>T, p.(Arg97Leu), not present in population databases and predicted to be damaging to protein function, was identified in a family with thoracic aortic disease and no evidence of HHT or JPS. Cellular studies revealed that the SMAD4 p.(Arg97Leu) alteration increased SMAD4 ubiquitination and 26S proteasome-mediated protein degradation. Smooth muscle cells (SMCs) infected with lentivirus expressing the SMAD4 p.(Arg97Leu) variant demonstrated reduced contractile protein gene expression when compared to that of wild-type SMAD4. In addition, two rare variants were identified in individuals with early age of onset of thoracic aortic dissection. These results suggest that SMAD4 rare missense variants can lead to thoracic aortic disease in individuals who do not have JPS or HHT.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Família , Mutação de Sentido Incorreto , Proteína Smad4 , Substituição de Aminoácidos , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteína Smad4/genética , Proteína Smad4/metabolismo , Ubiquitinação/genéticaRESUMO
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/químicaRESUMO
PURPOSE: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. METHODS: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. RESULTS: Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK. CONCLUSION: These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.
Assuntos
Doenças da Aorta/genética , Proteínas de Ligação ao Cálcio/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Quinase de Cadeia Leve de Miosina/genética , Adulto , Idoso , Dissecção Aórtica , Aorta/patologia , Aorta/cirurgia , Doenças da Aorta/patologia , Doenças da Aorta/cirurgia , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , GravidezRESUMO
Nuclei are actively positioned and anchored to the cytoskeleton via the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. We identified mutations in the Parkin-like E3 ubiquitin ligase Ariadne-1 (Ari-1) that affect the localization and distribution of LINC complex members in Drosophila. ari-1 mutants exhibit nuclear clustering and morphology defects in larval muscles. We show that Ari-1 mono-ubiquitinates the core LINC complex member Koi. Surprisingly, we discovered functional redundancy between Parkin and Ari-1: increasing Parkin expression rescues ari-1 mutant phenotypes and vice versa. We further show that rare variants in the human homolog of ari-1 (ARIH1) are associated with thoracic aortic aneurysms and dissections, conditions resulting from smooth muscle cell (SMC) dysfunction. Human ARIH1 rescues fly ari-1 mutant phenotypes, whereas human variants found in patients fail to do so. In addition, SMCs obtained from patients display aberrant nuclear morphology. Hence, ARIH1 is critical in anchoring myonuclei to the cytoskeleton.
Assuntos
Aneurisma Aórtico/patologia , Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Mutação , Miócitos de Músculo Liso/patologia , Ubiquitina-Proteína Ligases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/metabolismo , Proteínas de Transporte/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Pré-Escolar , Citoesqueleto , Proteínas de Drosophila/genética , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Linhagem , Fenótipo , Ubiquitina-Proteína Ligases/genética , Adulto JovemRESUMO
The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs∗25 and p.Glu750∗) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-ß binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3-/- mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Predisposição Genética para Doença , Proteínas de Ligação a TGF-beta Latente/genética , Mutação/genética , Adulto , Idoso de 80 Anos ou mais , Animais , Pressão Sanguínea/genética , Feminino , Homozigoto , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , LinhagemRESUMO
PURPOSE: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. METHODS: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. RESULTS: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. CONCLUSION: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.
Assuntos
Actinas/genética , Aneurisma da Aorta Torácica/genética , Permeabilidade do Canal Arterial/genética , Oftalmopatias Hereditárias/genética , Midríase/genética , Adolescente , Adulto , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/fisiopatologia , Arginina/genética , Criança , Pré-Escolar , Permeabilidade do Canal Arterial/diagnóstico , Permeabilidade do Canal Arterial/diagnóstico por imagem , Permeabilidade do Canal Arterial/fisiopatologia , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/diagnóstico por imagem , Oftalmopatias Hereditárias/fisiopatologia , Predisposição Genética para Doença , Testes Genéticos , Humanos , Lactente , Prontuários Médicos , Músculo Liso/diagnóstico por imagem , Músculo Liso/fisiopatologia , Midríase/diagnóstico , Midríase/diagnóstico por imagem , Midríase/fisiopatologia , Adulto JovemRESUMO
Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-ß-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.
Assuntos
Displasia Fibromuscular/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Osso e Ossos/patologia , Braquidactilia/genética , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular , Exoma/genética , Feminino , Genes Recessivos , Heterozigoto , Homozigoto , Humanos , Deficiências da Aprendizagem/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Sindactilia/genética , SíndromeRESUMO
Acute aortic dissections are a preventable cause of sudden death if individuals at risk are identified and surgically repaired in a non-emergency setting. Although mutations in single genes can be used to identify at-risk individuals, the majority of dissection case subjects do not have evidence of a single gene disorder, but rather have the other major risk factor for dissections, hypertension. Initial genome-wide association studies (GWASs) identified SNPs at the FBN1 locus associated with both thoracic aortic aneurysms and dissections. Here, we used the Illumina HumanExome array to genotype 753 individuals of European descent presenting specifically with non-familial, sporadic thoracic aortic dissection (STAD) and compared them to the genotypes of 2,259 control subjects from the Atherosclerosis Risk in Communities (ARIC) study matched for age, gender, and, for the majority of cases, hypertension. SNPs in FBN1, LRP1, and ULK4 were identified to be significantly associated with STAD, and these results were replicated in two independent cohorts. Combining the data from all cohorts confirmed an inverse association between LRP1 rs11172113 and STAD (p = 2.74 × 10(-8); OR = 0.82, 95% CI = 0.76-0.89) and a direct association between ULK4 rs2272007 and STAD (p = 1.15 × 10(-9); OR = 1.35, 95% CI = 1.23-1.49). Genomic copy-number variation analysis independently confirmed that ULK4 deletions were significantly associated with development of thoracic aortic disease. These results indicate that genetic variations in LRP1 and ULK4 contribute to risk for presenting with an acute aortic dissection.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteínas Serina-Treonina Quinases/genética , Idoso , Dissecção Aórtica/complicações , Aneurisma da Aorta Torácica/complicações , Aterosclerose/genética , Estudos de Casos e Controles , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Europa (Continente)/etnologia , Exoma/genética , Feminino , Fibrilina-1/genética , Deleção de Genes , Genótipo , Humanos , Hipertensão/complicações , Hipertensão/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Fatores de Transcrição Forkhead/genética , Adulto , Dissecção Aórtica/metabolismo , Dissecção Aórtica/patologia , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Apoptose , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/patologia , Mutação de Sentido Incorreto , Miócitos de Músculo Liso/fisiologia , Linhagem , Proteína Supressora de Tumor p53/genética , Remodelação Vascular , Peixe-ZebraRESUMO
RATIONALE: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families. OBJECTIVES: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections. METHODS AND RESULTS: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections. CONCLUSIONS: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Mutação/genética , Proteína-Lisina 6-Oxidase/genética , Adulto , Idoso , Sequência de Aminoácidos , Dissecção Aórtica/diagnóstico , Aneurisma da Aorta Torácica/diagnóstico , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , LinhagemRESUMO
We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-ß signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-ß signaling pathway exhibit arterial aneurysms and dissections as key features.
Assuntos
Aneurisma/genética , Dissecção Aórtica/genética , Artérias/metabolismo , Artérias/patologia , Mutação , Proteína Smad2/genética , Adulto , Alelos , Aneurisma/diagnóstico , Aneurisma/metabolismo , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/metabolismo , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas , Análise de Sequência de DNA , Proteína Smad2/química , Adulto JovemRESUMO
BACKGROUND: ACTA2 mutations are the major cause of familial thoracic aortic aneurysms and dissections. We sought to characterize these aortic diseases in a large case series of individuals with ACTA2 mutations. METHODS AND RESULTS: Aortic disease, management, and outcome associated with the first aortic event (aortic dissection or aneurysm repair) were abstracted from the medical records of 277 individuals with 41 various ACTA2 mutations. Aortic events occurred in 48% of these individuals, with the vast majority presenting with thoracic aortic dissections (88%) associated with 25% mortality. Type A dissections were more common than type B dissections (54% versus 21%), but the median age of onset of type B dissections was significantly younger than type A dissections (27 years versus 36 years). Only 12% of aortic events were repair of ascending aortic aneurysms, which variably involved the aortic root, ascending aorta, and aortic arch. Overall, cumulative risk of an aortic event at age 85 years was 0.76 (95% confidence interval, 0.64-0.86). After adjustment for intrafamilial correlation, sex and race, mutations disrupting p.R179 and p.R258 were associated with significantly increased risk for aortic events, whereas p.R185Q and p.R118Q mutations showed significantly lower risk of aortic events compared with other mutations. CONCLUSIONS: ACTA2 mutations are associated with high risk of presentation with an acute aortic dissection. The lifetime risk for an aortic event is only 76%, suggesting that additional environmental or genetic factors play a role in expression of aortic disease in individuals with ACTA2 mutations.