Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter ≥ 4.0 cm in adults, or a Z-score ≥ 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.

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Гранулематоз с полиангиитом (ГПА)-системный васкулит с преимущественным поражением сосудов мелкого и среднего калибра (капилляров, венул, артериол, артерий, вен) и некротизирующим гранулематозным воспалением с вовлечением верхних и нижних дыхательных путей [1]. Вместе с микроскопическим полиангиитом и синдромом Черджа-Стросса принадлежит к группе васкулитов, ассоциированных с антинейтрофильными цитоплазматическими антителами [1, 2]. Данное заболевание можно также отнести к гранулематозным болезням неизвестной этиологии, поскольку деструктивные процессы в артериях мелкого калибра сочетаются с грануле

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The literature on the etiology, pathogenesis, clinical manifestations and pathology, basic approaches to the treatment of congenital and acquired pathological deformation of the internal carotid artery has been analyzed. The review discusses the possible risk factors and diseases that lead to the development of pathological deformations as well as existing hypotheses of pathogenesis. Open and unresolved issues of the etiology and pathogenesis of this disease are identified. The disputable issues on the emergence and development of vascular deformations in children, young people and elderly are discussed. The authors posit a hypothesis that congenital and acquired pathological deformations are different diseases which differ by etiology, pathogenesis, clinical and pathomorphological picture, prognosis, approaches to diagnosis and treatment; the relationship between them has not been proved.