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- Homozygous Familial Hypercholesterolaemia: Insights From Portuguese Cases and Follow-up DataPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Miranda, Beatriz; Chora, Joana Rita; Aguiar, Patrício; Amaro, Mário; Bruges, Margarida; Ferreira, Sofia; Furtado, António; Gaspar, Ana; Gonçalves, Filipa Sousa; Lobarinhas, Goreti; Lourenço, Guilherme; Martins, Paula; Antunes, Sofia Moura; Palma, Isabel; Rato, Quitéria; Torres, Diogo; Rico, Miguel Toscano; Travessa, André; Bourbon, MafaldaAims: Present the clinical/genetic and follow-up data on individuals genetically identified with HoFH.
- Familial Chylomicronemia Syndrome: Clinical and Molecular Data From a Portuguese CohortPublication . Alves, Ana Catarina; Ferreira, Maria; Ferreira, Ana Cristina; Padeira, Gonçalo; Gaspar, Ana; Duarte, João Sequeira; Rato, Quitéria; Gonçalves, Filipa Sousa; Aguiar, Patrício; Cruz, Diogo; Raimundo, Anabela; Bourbon, MafaldaFamilial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive disorder caused by biallelic variants in LPL, APOC2, GPIHBP1, APOA5, or LMF1. These defects impair triglyceride-rich lipoprotein hydrolysis, leading to xanthomas, abdominal pain, hepatomegaly, lipemia retinalis, and recurrent pancreatitis. Multifactorial Chylomicronemia Syndrome (MCS) often results from monoallelic variants in these genes and/or a high polygenic risk score, presenting a similar phenotype; thus, genetic testing is required for accurate differentiation. This study aimed to clinically and genetically characterize 45 individuals with severe hypertriglyceridemia in Portugal. Lipid profile and molecular analysis of the five canonical genes were performed. Moulin’s score was applied in 17 cases. The mean pretreatment triglyceride level was 2570 mg/dL. Sixteen individuals had pancreatitis, four had hepatomegaly, and three both conditions. Ten cases carried biallelic variants: five in LPL (three identical, two compound heterozygous), one in APOC2, one frameshift in LMF1, one frameshift and one stop in APOA5, and one total exon 4 deletion in GPIHBP1 (all identical variants). All were classified as “very likely FCS” by Moulin’s score. Twenty-one individuals had heterozygous variants in LPL, APOA5, LMF1, and GPIHBP1 and were considered MCS; three of them also scored as “very likely FCS.” Ten patients had negative genetic studies (five scored as “unlikely FCS”), and four remain under investigation. Early recognition of FCS is crucial to prevent life-threatening complications. A confirmed molecular diagnosis enables precise distinction between FCS and MCS, improving management and prognosis. These findings underscore the importance of incorporating genetic testing into the diagnostic workup of severe hypertriglyceridemia in Portugal.
- From Uncertainty To Diagnosis: Functional Reclassification Of LDLR Variants In Familial HypercholesterolemiaPublication . Chora, Joana Rita; Islam, Mohammad Majharul; Alves, Ana Catarina; Pfisterer, Simon; Bourbon, MafaldaObjectives: Familial hypercholesterolaemia (FH) is a common disorder of lipid metabolism marked by an increased risk of premature atherosclerotic cardiovascular disease. While genetic testing confirms diagnosis, many LDLR variants are classified as variants of uncertain significance (VUS) due to lack of evidence, limiting clinical actionability. Functional assays can support reclassification, but conventional approaches are time-consuming. This study aims to use a high-throughput functional pipeline to evaluate LDLR VUS and improve diagnostic precision in FH. Methods: We analysed 133 LDLR VUS lacking functional evidence using an automated analysis platform based on multiplexed high-content imaging to quantify LDL uptake. Variants were classified based on uptake relative to wild-type: <70% for PS3_Supporting (pathogenic) and >90% for BS3_Supporting (benign), according to LDLR-specific ACMG/AMP guidelines. A subset of 46 “hot VUS” required only one supporting criterion to reach a likely benign or likely pathogenic classification. Results: Of the 133 variants, 53 showed <70% uptake and were assigned PS3_Supporting, while 41 showed >90% uptake and received BS3_Supporting. The remaining 39 variants exhibited intermediate activity (70–90%). Among the 46 hot VUS, 12 were reclassified as likely benign and 11 as likely pathogenic. An additional 43 variants are now one supporting criterion away from potential reclassification. Conclusions: High-throughput functional testing provides robust and rapid evidence for LDLR variant interpretation. By adding evidence about LDLR activity these assays contribute to resolve diagnostic uncertainty and enables earlier and more accurate diagnosis, optimizes cascade screening, and enables better risk stratification to inform treatment options. These findings support a shift toward personalised genomic medicine in lipid disorders, with direct implications for patient care and cardiovascular risk reduction.