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1.
Am J Med Genet A ; 188(5): 1448-1456, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35092149

RESUMEN

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.


Asunto(s)
Anomalías de los Vasos Coronarios , Síndrome de Ehlers-Danlos , Síndrome de Loeys-Dietz , Enfermedades Vasculares , Anomalías de los Vasos Coronarios/epidemiología , Anomalías de los Vasos Coronarios/genética , Síndrome de Ehlers-Danlos/genética , Predisposición Genética a la Enfermedad , Humanos , Síndrome de Loeys-Dietz/complicaciones , Síndrome de Loeys-Dietz/epidemiología , Síndrome de Loeys-Dietz/genética , Factores de Riesgo , Enfermedades Vasculares/congénito , Enfermedades Vasculares/epidemiología , Enfermedades Vasculares/genética
2.
Am J Hum Genet ; 102(4): 706-712, 2018 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-29625025

RESUMEN

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.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Predisposición Genética a la Enfermedad , Proteínas de Unión a TGF-beta Latente/genética , Mutación/genética , Adulto , Anciano de 80 o más Años , Animales , Presión Sanguínea/genética , Femenino , Homocigoto , Humanos , Masculino , Ratones , Persona de Mediana Edad , Linaje
3.
Am J Hum Genet ; 100(1): 21-30, 2017 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-27939641

RESUMEN

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.


Asunto(s)
Displasia Fibromuscular/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Mutación , Proteínas Nucleares/genética , Factores de Transcripción/genética , Adolescente , Adulto , Huesos/patología , Braquidactilia/genética , Puntos de Control del Ciclo Celular/genética , Proteínas de Ciclo Celular , Exoma/genética , Femenino , Genes Recesivos , Heterocigoto , Homocigoto , Humanos , Discapacidades para el Aprendizaje/genética , Masculino , Persona de Mediana Edad , Linaje , Sindactilia/genética , Síndrome
4.
Genet Med ; 22(2): 427-431, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31474762

RESUMEN

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.


Asunto(s)
Trastornos Cerebrovasculares/genética , Enfermedad de Moyamoya/genética , Adulto , Proteínas de Ciclo Celular/genética , Trastornos Cerebrovasculares/metabolismo , Niño , Preescolar , ADN Helicasas/genética , Discapacidades del Desarrollo/genética , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Metiltransferasas/genética , Metiltransferasas/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Persona de Mediana Edad , Mutación/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Secuenciación del Exoma/métodos
5.
J Vasc Surg ; 71(1): 149-157, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31353273

RESUMEN

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.


Asunto(s)
Colágeno Tipo III/genética , Análisis Mutacional de ADN , Síndrome de Ehlers-Danlos/diagnóstico , Mutación , Adolescente , Adulto , Estudios Transversales , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/genética , Femenino , Predisposición Genética a la Enfermedad , Alemania , Humanos , Italia , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Estados Unidos , Adulto Joven
6.
J Med Genet ; 56(4): 252-260, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30661052

RESUMEN

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.


Asunto(s)
Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Fenotipo , Proteína smad3/genética , Adolescente , Adulto , Anciano , Alelos , Sustitución de Aminoácidos , Aneurisma de la Aorta Torácica/complicaciones , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Dominios Proteicos/genética , Factores de Riesgo , Proteína smad3/química
7.
Am J Hum Genet ; 99(3): 762-769, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27569546

RESUMEN

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.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteínas Serina-Treonina Quinasas/genética , Anciano , Disección Aórtica/complicaciones , Aneurisma de la Aorta Torácica/complicaciones , Aterosclerosis/genética , Estudios de Casos y Controles , Estudios de Cohortes , Variaciones en el Número de Copia de ADN/genética , Europa (Continente)/etnología , Exoma/genética , Femenino , Fibrilina-1/genética , Eliminación de Gen , Genotipo , Humanos , Hipertensión/complicaciones , Hipertensión/genética , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
8.
Genet Med ; 21(1): 144-151, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29925964

RESUMEN

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.


Asunto(s)
Enfermedades de la Aorta/genética , Proteínas de Unión al Calcio/genética , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Quinasa de Cadena Ligera de Miosina/genética , Adulto , Anciano , Disección Aórtica , Aorta/patología , Aorta/cirugía , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/cirugía , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Embarazo
9.
J Vasc Surg ; 70(3): 718-723, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30871887

RESUMEN

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.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/genética , Mutación , Adolescente , Adulto , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/enzimología , Disección Aórtica/terapia , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/enzimología , Aneurisma de la Aorta Torácica/terapia , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos , Adulto Joven
10.
J Vasc Surg ; 70(5): 1543-1554, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31126764

RESUMEN

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.


Asunto(s)
Aneurisma/epidemiología , Aorta/patología , Arterias/patología , Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aneurisma/genética , Aneurisma/patología , Aneurisma/terapia , Aorta/cirugía , Arterias/cirugía , Niño , Preescolar , Colágeno Tipo III/metabolismo , Estudios Transversales , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Embolización Terapéutica/estadística & datos numéricos , Procedimientos Endovasculares/métodos , Procedimientos Endovasculares/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Pruebas Genéticas/estadística & datos numéricos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación Missense , Estudios Retrospectivos , Adulto Joven
11.
Am J Hum Genet ; 96(1): 170-7, 2015 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-25557781

RESUMEN

Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Metionina Adenosiltransferasa/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Disección Aórtica/genética , Animales , Válvula Aórtica/anomalías , Enfermedad de la Válvula Aórtica Bicúspide , Exoma , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Enfermedades de las Válvulas Cardíacas/genética , Humanos , Masculino , Metionina Adenosiltransferasa/metabolismo , Persona de Mediana Edad , Mutación , Linaje , Conformación Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adulto Joven , Pez Cebra/genética
12.
Genet Med ; 20(10): 1206-1215, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29300374

RESUMEN

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.


Asunto(s)
Actinas/genética , Aneurisma de la Aorta Torácica/genética , Conducto Arterioso Permeable/genética , Enfermedades Hereditarias del Ojo/genética , Midriasis/genética , Adolescente , Adulto , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/fisiopatología , Arginina/genética , Niño , Preescolar , Conducto Arterioso Permeable/diagnóstico , Conducto Arterioso Permeable/diagnóstico por imagen , Conducto Arterioso Permeable/fisiopatología , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/diagnóstico por imagen , Enfermedades Hereditarias del Ojo/fisiopatología , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Lactante , Registros Médicos , Músculo Liso/diagnóstico por imagen , Músculo Liso/fisiopatología , Midriasis/diagnóstico , Midriasis/diagnóstico por imagen , Midriasis/fisiopatología , Adulto Joven
13.
Circ Res ; 118(6): 928-34, 2016 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-26838787

RESUMEN

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.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Mutación/genética , Proteína-Lisina 6-Oxidasa/genética , Adulto , Anciano , Secuencia de Aminoácidos , Disección Aórtica/diagnóstico , Aneurisma de la Aorta Torácica/diagnóstico , Femenino , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje
14.
Hum Mutat ; 36(12): 1145-9, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26247899

RESUMEN

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.


Asunto(s)
Aneurisma/genética , Disección Aórtica/genética , Arterias/metabolismo , Arterias/patología , Mutación , Proteína Smad2/genética , Adulto , Alelos , Aneurisma/diagnóstico , Aneurisma/metabolismo , Disección Aórtica/diagnóstico , Disección Aórtica/metabolismo , Biología Computacional/métodos , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Dominios y Motivos de Interacción de Proteínas , Análisis de Secuencia de ADN , Proteína Smad2/química , Adulto Joven
15.
Stroke ; 45(11): 3200-7, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25278557

RESUMEN

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States. METHODS: We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families. RESULTS: RNF213 p.R4810K was identified in 56% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant. CONCLUSIONS: These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.


Asunto(s)
Etnicidad/genética , Variación Genética/genética , Enfermedad de Moyamoya/genética , Vigilancia de la Población , Ubiquitina-Proteína Ligasas/genética , Adenosina Trifosfatasas , Adolescente , Adulto , Niño , Estudios de Cohortes , Etnicidad/etnología , Femenino , Humanos , Masculino , Enfermedad de Moyamoya/diagnóstico , Enfermedad de Moyamoya/etnología , Vigilancia de la Población/métodos , Adulto Joven
16.
Am J Med Genet A ; 164A(1): 106-12, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24243736

RESUMEN

Mutations in ACTA2 predispose to thoracic aortic aneurysms and dissection as well as coronary artery and cerebrovascular disease. Here we examined the risk of aortic dissections, stroke and myocardial infarct with pregnancy in women with ACTA2 mutations. Of the 53 women who had a total of 137 pregnancies, eight had aortic dissections in the third trimester or the postpartum period (6% of pregnancies). One woman also had a myocardial infarct that occurred during pregnancy that was independent of her aortic dissection. Compared to the population-based frequency of peripartum aortic dissections of 0.6%, the rate of peripartum aortic dissections in women with ACTA2 mutations is much higher (8 out of 39; 20%). Six of these dissections initiated in the ascending aorta (Stanford type A), three were fatal. Three women had ascending aortic dissections at diameters less that 5.0 cm (range 3.8-4.7 cm). Aortic pathology showed mild to moderate medial degeneration of the aorta in three women. Of note, five of the women had hypertension either during or before the pregnancy. In summary, the majority of women with ACTA2 mutations did not have aortic or other vascular complications with pregnancy. However, these findings show that pregnancy is associated with significant risk for aortic dissection in women with ACTA2 mutations. Women with ACTA2 mutations who are planning to get pregnant should be counseled about this risk of aortic dissection, and proper clinical management should be initiated to reduce this risk.


Asunto(s)
Actinas/genética , Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Mutación , Disección Aórtica/diagnóstico , Disección Aórtica/patología , Aorta Torácica/patología , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Embarazo , Tomografía Computarizada por Rayos X
17.
PLoS Genet ; 7(6): e1002118, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21698135

RESUMEN

Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0 × 10⁻5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Duplicación Cromosómica/genética , Cromosomas Humanos Par 16/genética , Adulto , Anciano , Disección Aórtica/patología , Aorta/patología , Aneurisma de la Aorta Torácica/patología , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Linaje , Fenotipo , Factores de Riesgo
18.
Am J Hum Genet ; 87(6): 743-56, 2010 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-21092924

RESUMEN

Thoracic aortic aneurysms and dissections (TAAD) cause significant morbidity and mortality, but the genetic origins of TAAD remain largely unknown. In a genome-wide analysis of 418 sporadic TAAD cases, we identified 47 copy number variant (CNV) regions that were enriched in or unique to TAAD patients compared to population controls. Gene ontology, expression profiling, and network analysis showed that genes within TAAD CNVs regulate smooth muscle cell adhesion or contractility and interact with the smooth muscle-specific isoforms of α-actin and ß-myosin, which are known to cause familial TAAD when altered. Enrichment of these gene functions in rare CNVs was replicated in independent cohorts with sporadic TAAD (STAAD, n = 387) and inherited TAAD (FTAAD, n = 88). The overall prevalence of rare CNVs (23%) was significantly increased in FTAAD compared with STAAD patients (Fisher's exact test, p = 0.03). Our findings suggest that rare CNVs disrupting smooth muscle adhesion or contraction contribute to both sporadic and familial disease.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Adhesión Celular/genética , Dosificación de Gen , Músculo Liso Vascular/patología , Adulto , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Torácica/patología , Aneurisma de la Aorta Torácica/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/genética , Músculo Liso Vascular/fisiopatología
19.
Am J Med Genet A ; 161A(1): 185-91, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23239472

RESUMEN

Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-ß-related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis syndrome (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and features of Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.


Asunto(s)
Aorta/fisiopatología , Aneurisma de la Aorta Torácica/etiología , Poliposis Intestinal/genética , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditaria/genética , Adulto , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/genética , Niño , Ecocardiografía , Femenino , Fibrilina-1 , Fibrilinas , Humanos , Poliposis Intestinal/complicaciones , Poliposis Intestinal/diagnóstico , Masculino , Síndrome de Marfan/genética , Proteínas de Microfilamentos/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Transducción de Señal , Proteína smad3/genética , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Factor de Crecimiento Transformador beta/genética
20.
Circ Res ; 109(6): 680-6, 2011 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-21778426

RESUMEN

RATIONALE: Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner. OBJECTIVE: To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants. METHODS AND RESULTS: A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers. CONCLUSIONS: SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Mutación del Sistema de Lectura/genética , Aneurisma Intracraneal/genética , Proteína smad3/genética , Disección Aórtica/diagnóstico , Aneurisma de la Aorta Torácica/diagnóstico , Estudios de Cohortes , Femenino , Genes Dominantes/genética , Humanos , Aneurisma Intracraneal/diagnóstico , Masculino , Linaje , Análisis de Secuencia de ADN/métodos
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