DPSPDNT - Apresentações orais em encontros internacionais
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Browsing DPSPDNT - Apresentações orais em encontros internacionais by Author "Alves, Ana Catarina"
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- ABCG5 and ABCG8 variants associated to sitosterolemia in ClinVar – state of artPublication . Miranda, Beatriz Raposo; Alves, Ana Catarina; Bourbon, MafaldaSitosterolemia is a rare lipid disorder characterized by the accumulation of plant sterols in the blood, which can lead to several cardiovascular complications. This autosomal recessive disorder is due to pathogenic alterations in ABCG5 and ABCG8 genes. We aimed to assess ClinVar information regarding ABCG5/8 variants possibly causing sitosterolemia. ClinVar was consulted, and all variants submitted as related to “sitosterolemia” were considered (even if some of these were also associated with other phenotypes such as “cardiovascular phenotype”). ClinVar review status of two stars (multiple submissions, no conflicts), one star (single submissions or conflicting interpretations) and no stars (no assertion criteria provided) were considered. The file extracted for ABCG5 analysis contained 295 variants and the file extracted for ABCG8 contained 138 variants. In both files appeared variants mentioning both genes ABCG5/ABCG8 (=11). These were not considered for the descriptive analysis to avoid overcounting. Concerning ABCG5 variants (n=295), 24 are classified as pathogenic/likely pathogenic (3 with review status of two stars, 7 with one, and 6 with no stars); 67 as benign/likely benign (25 with two stars and 42 with one star). Additionally, 160 were classified as variants of uncertain significance (VUS) (61 with two stars, 98 with one, and 1 with no stars), and 44 have conflicting interpretations of pathogenicity (review status of one star). In the ABCG8 variants file (n=138), 16 are classified as pathogenic/likely pathogenic (7 with review status of two stars, 5 with one star, and 4 with no stars); and 26 as benign/likely benign (all with two stars). Additionally, 59 were found classified as VUS (28 with two stars and 31 with one star), and 37 have conflicting interpretations of pathogenicity (review status of one star). Despite there is information in ClinVar about these variants being found in homozygosity/compound heterozygosity in sitosterolemia patients (enabling a genotype-phenotype analysis), the great majority of variants in both genes lack other kind of information as functional characterization and in silico prediction analysis. ClinVar constitutes a fundamental tool for data sharing and to be consulted to know if a specific variant has been reported elsewhere but lacks other important information for variant classification. Although the majority are nonsense variants there are still many missense variants that need other type of information to be classified as pathogenic and this poses an important gap in sitosterolemia diagnosis. It remains crucial to improve the classification and knowledge of ABCG5/8 variants since the correct genetic diagnosis of sitosterolemia is vital for a personalized treatment.
- Impact of functional studies on updating the classification of genetic variants in familial hypercholesterolemiaPublication . Alves, Ana CatarinaAbout familial hypercholesterolemia and the impact of functional studies on updating the classification of its genetic variants.
- Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemiaPublication . Alves, Ana Catarina; Etxebarria, Aitor; Soutar, Anne Katherine; Martin, Cesar; Bourbon, Mafalda
- Sitosterolemia in Iberoamerican countries: new cases and phenotype genotype analysisPublication . Alves, Ana CatarinaIntroduction: Sitosterolemia is an autosomal recessive disorder caused by variations in ABCG5/8 genes and characterized by severely elevated plasma plant sterols, associated with xanthomas and premature cardiovascular disease. The aim of this study is to present 12 clinical cases of sitosterolemia in Iberoamerican countries. Methods: We report 11 index cases, and 4 relatives identified by cascade screening. Clinical and laboratory characteristics of individuals were determined in different countries. All individuals were sequenced for the ABCG5/8 genes in Portugal or in the country corresponding. Results: The geographical distribution of the 15 cases is as follows: seven from Spain (six compound heterozygous and one true homozygous, all in ABCG8); four from Portugal ( two true homozygous, in ABCG8, one in ABCG5 and one compound heterozygous in ABCG8); one from Argentina (true homozygous in ABCG8) and three from Uruguay (all true homozygous in ABCG8). Four index cases (~57%) and two of the relatives (40%) were diagnosed in childhood, the remaining identified as adults. Six index cases present variants in ABCG8 gene (two missense and four nonsense variants) and only one presents a homozygosity in the ABCG5 gene (frameshift variant). Conclusions: The eight variants identified in this study in ABCG8 and the one in the ABCG5 genes, indicate the genetic heterogeneity of sitosterolemia in Iberoamerican countries. The treatment for sitosterolemia is specific and completely different from the rest of hypercholesterolemias, so a correct and timely diagnosis is crucial to avoid delays in treatment that could lead to poor clinical outcomes.