Browsing 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.
- Adult cascade screening versus child reverse cascade screening in Familial HypercholesterolemiaPublication . Miranda, Beatriz Raposo; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, Mafalda; on behalf of the Portuguese FH Study investigatorsFamilial hypercholesterolemia (FH) is a common inherited lipid disorder that predisposes to cardiovascular disease (CVD). Despite most cascade screening programs are initiated by adult index cases, reverse cascade screening pediatric index cases is starting to be described. Therefore, we aimed to assess the outcome of adult cascade screening and child reverse cascade screening strategies in families from the Portuguese FH Study (PFHS). The PFHS database was consulted, and 423 index cases genetically identified with FH (224 adults and 199 children) and their 997 relatives referred to the PFHS were analysed. From 224 adults with FH, 485 relatives were enrolled for cascade screening and 290 were identified with FH. From 199 paediatric cases with FH, 512 relatives were screened and 286 were identified with FH. Child reverse cascade screening presented a slightly higher diagnostic rate than adult cascade screening, 1.44 vs 1.29 new cases with FH per index case, and the age of the relatives identified was younger, 29 vs 37 years. For 94% of index children, relatives were referred (2.56 relatives per index), in contrast with the adult cohort whereas only 70% were referred with family-members (2.17 relatives per index). Overall, both screening approaches constitute valuable tools to identify new cases with FH, but the child reverse cascade screening creates the opportunity for more relatives to be tested at a younger age. It is crucial to improve relatives' recruitment rate since early identification allows a correct FH diagnosis and treatment to prevent CVD.
- Aplicabilidade da fórmula Martin‐Hopkins e comparação com a fórmula Friedewald na estimativa do colesterol LDL na população do estudo e_CORPublication . Ferrinho, Cátia; Alves, Ana Catarina; Bourbon, Mafalda; Duarte, SequeiraIntrodução: O colesterol LDL (cLDL) é essencial na abordagem do risco de doenças cardiovasculares. Desde 1972 é utilizada a fórmula de Friedewald para estimativa da concentração do cLDL, com algumas limitações. Foi sugerida, em 2013, por Martin et al., uma fórmula semelhante que permite melhor exatidão no cálculo do cLDL. Objetivo: Mostrar aplicabilidade da nova fórmula, que nomeámos fórmula Martin‐Hopkins, na população portuguesa e comparar com a fórmula Friedewald utilizando o cLDL direto. Material e métodos: Estudo transversal, incluindo 1689 participantes do estudo e_COR. Aplicámos as fórmulas Martin‐Hopkins e Friedewald para a estimativa de cLDL (cLDL‐M e cLDL‐F). A fórmula Friedewald não foi aplicada em 12 casos por triglicéridos ≥ 400 mg/dL. Foi realizada a determinação direta do cLDL (cLDL‐D). Resultados apresentados em mediana e amplitude interquartil. Nível de significância aceite p < 0,05. Resultados: Dos participantes, 50,2% eram sexo masculino e mediana de 51 (34) anos. O cLDL‐D foi 117,0 (44,0) mg/dL, cLDL‐M foi 114,6 (43,7) mg/dL e cLDL‐F foi 113,8 (43,2) mg/dL. O coeficiente de Spearman (ρ) entre cLDL‐M/cLDL‐D foi 0,987 e entre cLDL‐F/cLDL‐D foi 0,983, p = 0,001. Esta forte correlação manteve‐se no grupo com diabetes mellitus (cLDL‐M/LDL‐D ρ = 0,987; cLDL‐F/cLDL‐D ρ = 0,978, p = 0,001) e hipertrigliceridemia (cLDL‐M/LDL‐D ρ = 0,983; cLDL‐F/cLDL‐D ρ = 0,982, p = 0,001). Na análise de concordância, o maior valor de κ = 0,90 foi obtido para cLDL‐M quando cLDL‐D < 100 mg/dL. Conclusão: A fórmula Martin‐Hopkins teve um bom desempenho e aplicabilidade, mostrando superioridade em relação à fórmula Friedewald, sobretudo para valores de cLDL‐D < 100 mg/dL, diabetes mellitus e hipertrigliceridemia.
- APOB Variants Spectrum and Functional Characterization in Portuguese Patients with Familial Hypercholesterolaemia PhenotypePublication . Ferreira, Maria Rafael Simões do Carmo; Alves, Ana Catarina; Rebelo, Maria TeresaFamilial hypercholesterolaemia (FH) is an autosomal semi dominant disorder of lipid metabolism clinically characterized by increased levels of circulating LDL cholesterol and associated with elevated cardiovascular risk. The genetic diagnosis is usually based on the analysis of LDLR, APOB, and PCSK9 genes. APOB variants are responsible for 5-10% of FH cases, and the variant spectrum of APOB has increased due to sequencing of the whole gene through Next Generation Sequencing, consequently increasing the number of variants that need to be functionally assessed. This dissertation aimed to verify the correlation between phenotype and genotype in individuals from the Portuguese FH Study, as well as create a database including all APOB variants found up to date in this study. Moreover, it was intended to characterize two APOB variants identified in subjects from this cohort. Graphics regarding LDL cholesterol levels were designed for index cases FH positive and negative and relatives FH positive. The variants previously detected by NGS were confirmed by PCR and Sanger sequencing, and cascade screening was carried out in families. All APOB variants with MAF <1% were gathered into a database. LDL from index cases and relatives was separated using sequential ultracentrifugation and labelled with FITC for uptake assessment by flow cytometry in CHO-ldlA7 cells, and proliferation assays were performed with U937 cells. A definite diagnosis was possible for 4 individuals carrying known pathogenic variants, and c.6639_6641del/p.(Asp2213del) and c.10121T>C/p.(Ile3374Thr) alterations from exon 26 were functionally assessed. In vitro studies showed a neutral effect on the apoB function for these variants. Furthermore, 143 different variants were discovered located throughout the whole gene, of which more than 90% were variants of uncertain significance. Functional studies, combined with the association between phenotype and genotype, allow a better and more personalized treatment according to the needs of each individual.
- APOB/APOA-I ratio and major cardiovascular risk factors in azores and Lisbon populations – a comparison studyPublication . Ferin, Rita; Lima, Ana; Baptista, José; Alves, Ana Catarina; Bourbon, Mafalda; Pavão, Maria LeonorIn the Azores Archipelago age adjusted death rates from coronary artery disease (CAD) are two-fold higher than in mainland Portugal. Also, there is not a registered central database on the prevalent risk factors for atherosclerosis (AT), the major cause of cardiovascular disease (CVD). Those factors can diverge in different populations, due to their genetic and/or particular exposure to environmental factors.
- Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers for the correct assessment of monogenic dyslipidemiaPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Aguiar, Pedro; Bourbon, Mafalda
- Cascade Screening in Familial Hypercholesterolemia: Adult cascade screening versus CHILD reverse cascade screeningPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is an inherited lipid disorder that increases the risk of developing cardiovascular disease (CVD). Despite most cascade screening programs are initiated by adult index cases, reverse cascade screening pediatric index cases is starting to be described. Therefore, in this work, we aimed to assess the outcome of both creening strategies (adult cascade screening and child reverse cascade screening) in families from the Portuguese FH Study (PFHS). The PFHS database was consulted, and 423 index cases genetically identified with FH (224 adults and 199 children) and their 997 relatives referred to the PFHS were analysed. From 224 adults with FH, 485 relatives were enrolled for cascade screening and 290 were identified with FH. From 199 paediatric cases with FH, 512 relatives were screened and 286 were identified with FH. Child reverse cascade screening presented a slightly higher diagnostic rate than adult cascade screening, 1.44 vs 1.29 new cases with FH per index case, and the age of the relatives identified was younger, 29 vs 37 years. For 94% of index children, relatives were referred (2.56 relatives per index), in contrast with the adult cohort whereas only 70% were referred with family-members (2.17 relatives per index). Overall, both screening approaches constitute valuable tools to identify new cases with FH, but the child reverse cascade screening notably creates the opportunity for more relatives to be tested at a younger age. However, it remains crucial to improve relatives' recruitment rate since early identification allows a correct FH diagnosis and treatment to prevent CVD.
- Characterization of the First PCSK9 Gain of Function HomozygotePublication . Alves, Ana Catarina; Etxebarria, Aitor; Medeiros, Ana Margarida; Benito-Vicente, Asier; Thedrez, Aurélie; Passard, Maxime; Croyal, Mikaël; Martin, Cesar; Lambert, Gilles; Bourbon, MafaldaGain of function (GOF) mutations in proprotein convertase subtilisin kexin type 9 (PCSK9) are a rare cause of familial hypercholesterolemia (FH). We identified a child with a clinical diagnosis of FH with 2 novel putative PCSK9 GOF missense variants (p.[(Ala62Asp)]; [(Pro467Ala)]), and no mutation in the low-density lipoprotein (LDL) receptor (LDLR) or in apolipoprotein B100 (APOB) genes. The proband was referred to the Portuguese FH Study (1) at age 11 and presented a total cholesterol of 316 mg/dl and low-density lipoprotein cholesterol (LDL-C) of 234 mg/dl on a strict diet. The phenotype presented by all PCSK9 heterozygous carriers within this large pedigree is similar to APOB heterozygous carriers (LDL-C, 198.75 ± 14.98 mg/dl vs. LDL-C, 211.57 ± 42.02 mg/dl; p = 0.227) but significantly different than heterozygous LDLR carriers (LDL-C, 198.75 ± 14.98 mg/dl vs. LDL-C, 230.63 ± 76.50 mg/dl; p = 0.012) when comparing the relatives’ phenotype in our cohort.
- Classification Methods Applied to Familial Hypercholesterolemia Diagnosis at Pediatric Age: Comparison of Simon Broome Criteria with Modified Decision Tree ModelsPublication . Albuquerque, João; Medeiros, Ana Margarida; Alves, Ana Catarina; Antunes, Marília; Bourbon, MafaldaIntroduction: Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, resulting in severe dyslipidemia and increased CVD risk. Simon Broome (SB) criteria for the diagnostic of FH are among the most frequently used in clinical setting, and are based on elevated total cholesterol (TC) and low density lipoprotein (LDLc) cholesterol levels, presence of tendinous xanthomas and family history [1]. The molecular diagnosis that confirms this diagnosis reveals, however, a high false positive rate when following these criteria, which can represent a heavy burden in terms of healthcare costs. The main purpose of this work was to develop alternative classification models for FH diagnosis, based on different decision tree (DT) algorithms, using commonly available biochemical markers as predictors.
- Classification methods applied to the diagnosis of pediatric patients with familial hypercholesterolemia: comparison of Simon Broome criteria with logistic regression and modified decision tree modelsPublication . Albuquerque, João; Antunes, Marília; Alves, Ana Catarina; Medeiros, Ana Margarida; Bourbon, MafaldaFamilial Hypercholesterolemia (FH) is a monogenic disorder of lipid metabolism, resulting in severe dyslipidemia and increased cardiovascular disease risk. Simon Broome (SB) criteria for the diagnostic of FH are among the most frequently used in clinical setting, and are based on elevated total cholesterol (TC) and low density lipoprotein (LDLc) cholesterol levels, presence of tendinous xanthomas and family history, although only genetic testing can confirm the diagnosis. According to the Portuguese Study of Familial Hypercholesterolemia (EPHF), only around 42% of the patients with clinical criteria reveal a positive diagnostic for FH, a high false positive rate that represents a heavy burden in terms of healthcare costs. The main purpose of this work was to develop alternative classification models for FH diagnosis based on two different methods, logistic regression (LR) and decision trees (DT), using several biochemical indicators as predictor variables. Both models were compared with SB clinical criteria in terms of accuracy and efficiency, through bootstrap resampling techniques.