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- DLCN-PED – A New Proposal For Clinical Diagnosis Of Children And Young People With FHPublication . Miranda, Beatriz; Kafol, Jan; Humphries, Steve E.; Freiberger, Tomas; Medeiros, Ana Margarida; Sikonja, Jaka; Alves, Ana Catarina; Groselj, Urh; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, and premature cardiovascular disease (CVD). The most used clinical diagnostic criteria to identify FH are the Dutch Lipid Clinic Network-(DLCN) and Simon Broome-(SB), being SB the only with specific criteria for children. This work aims to propose an adaptation of DLCN criteria, for children and young people (DLCN-PED) and assess the performance of this adaptation in the Portuguese and Slovenian FH registries. DLCN-PED includes data on clinical examinations, lipid profile, familial history of CVD and hypercholesterolemia. We propose that those with a DLCN-PED score3 should be referred for genetic testing. Index cases included were studied with an NGS panel including at least the three FH-causing genes prior to evaluation with DLCN-PED This work includes 1696 patients (Portugal=340, Slovenia=1356): 29% FH-positives (presenting likely pathogenic/pathogenic variants in FH genes), 71% FH-negatives (no detection of pathogenic variants). Individuals with variants of uncertain significance were not included. Scores had a range between 0-17, 58% presenting a score between 2-4. Across DLCN-PED scores, we observe a distribution overlap for both FH groups: FH-negatives from 0-8 and FH-positives from 0-17. Overall, DLCN-PED3 presents higher sensitivity compared to SB (93% vs 81%) and slightly lower specificity (55% vs 79%). DLCN-PED6 presents lower sensitivity compared to SB (67% vs 81%) but an enhanced specificity (91% vs 79%). The different analysis suggests that score cutoffs should be adapted according to the screening approach intended (sensitivity and specificity trade-off). Compared to DLCN, the DLCN-PED shows an improved performance (p-value=0.024). Given the crucial role of clinical diagnosis in FH identification, we have shown that the proposed DLCN-PED performs better than the general DLCN and is similar to SB with the advantage that is possible to personalize the cut offs and so it could improve FH assessment worldwide.
- Evaluating Clinical Markers To Improve Selection Of Diabetes Patients For Genetic TestingPublication . Vaz, Margarida; Gaspar, Gisela; Dario, Paulo; Bourbon, MafaldaMaturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes caused by variants in one of 14 genes, each affecting glucose metabolism differently and leading to heterogeneous clinical presentations. Because of this variability, MODY is frequently misdiagnosed as type 1 or type 2 diabetes. In this work, the aim was to characterize patients with and without pathogenic MODY variants among participants of the Molecular Study of Monogenic Diabetes. Clinical data—age at diagnosis, blood glucose, HbA1c, and C-peptide—were analyzed using statistical tests (Shapiro and Wilcoxon). Among these parameters, only age at diagnosis differed significantly, with MODY patients being diagnosed earlier, likely due to the high prevalence of GCK-MODY in the cohort. C-peptide levels were within normal ranges in both groups. The study concludes that these common clinical markers are insufficient to reliably identify MODY cases, emphasizing the need for additional biomarkers and highlighting genetic testing as the only definitive diagnostic tool
- Familial Hypercholesterolemia (FH): 25 Years Of Findings In The Portuguese FH StudyPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaFamilial Hypercholesterolemia (FH) is a hereditary condition characterized by elevated LDL-C levels, which leads to increased risk of atherosclerosis and cardiovascular events. FH presents an estimated frequency of 1/300 and is expected to affect almost 33,000 Portuguese individuals. Therefore, this work summarizes the advances achieved in 25 years of diagnosis and investigation within the Portuguese FH Study (EPHF). A lipid profile and genetic diagnosis were performed for 1291 referred index cases fulfilling FH clinical criteria (523 children, 768 adults) and 2288 relatives. In 2017, a Next Generation Sequencing panel including FH genes (LDLR, APOB, PCSK9) and FH phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, ABCG8) was implemented. In approximately 40% (n=464) of the EPHF cohort, a genetic cause of FH was identified: 451 index cases with heterozygous FH (HeFH) and 13 with homozygous FH (HoFH). The majority of pathogenic variants were found in the LDLR gene (93%), compared with APOB (5%) and PCSK9 (2%) genes. Cascade screening allowed the identification of FH in 624 relatives (622 HeFH and 2 HoFH). Among adults with FH, 20% present cardiovascular disease (CVD) and 17% have premature CVD. Variants of uncertain significance in FH genes were identified in 63 index cases. Within 60% of the EPHF cohort (group of index cases where the genetic cause of hypercholesterolemia was not identified), 35% present hyper-Lp(a). Other monogenic causes of dyslipidemia were discovered during genetic analysis: 4 cases with lysosomal lipase deficiency (LIPA gene) and 4 cases with sitosterolemia (ABCG5 and/or ABCG8 genes). The genetic identification of FH corresponds to 3% of the expected number of individuals affected in Portugal. Nevertheless, other rare lipid metabolism disorders were identified. To overcome FH underdiagnosis in Portugal and to promote early diagnosis and treatment to prevent CDV complications, a cost-effective screening chip array is under development.
- Genetic Diagnosis of Familial Hypercholesterolaemia (FH) In Portugal: Insights from the Portuguese FH StudyPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaThis work summarises the outcomes of FH genetic testing in the PFHS.
- A Global Survey Of Genetic Testing Methods For Familial Hypercholesterolemia. A Study From The EAS FHSC RegistryPublication . Karungi, Irene, On behalf of the EAS FHSC Investigators; Chora, Joana Rita; Elshorbagy, A.; Stevens, C.A.T.; Vallejo-Vaz, A. J.; Ray, K. K.; Raal, F. J.; Humphries, S. E.; Freiberger, T.; Bourbon, M.Contexto: A hipercolesterolemia familiar (HF) é causada principalmente por variantes patogénicas nos genes LDLR, APOB ou PCSK9, levando a um LDL-C elevado ao longo da vida e a um aumento do risco de doenças cardiovasculares. Os testes genéticos oferecem um diagnóstico definitivo da HF, no entanto, falta uma abordagem padronizada para os métodos de teste genético da FH a nível global. Métodos: Foi enviado um inquérito estruturado a investigadores nacionais de 68 países ativos no registo da Colaboração de Estudos EAS-FH. Os domínios do inquérito incluíram critérios para encaminhamento para testes genéticos, técnicas de teste, triagem genética e interpretação da patogenicidade variante. Os dados foram analisados descritivamente, e foram feitas comparações entre casos índice e não-índice e países de rendimento elevado versus não elevado. Resultados: Dos 68 países convidados, 55 (81%) responderam. Entre os países com critérios clínicos estabelecidos para adultos (85%) e crianças (76%), a rede holandesa de clínicas de lípidos foi o critério mais utilizado para o encaminhamento de adultos e crianças (72% e 57%, respetivamente) para testes genéticos. Os critérios de Simon-Broome e MedPed foram usados com menor frequência, reportados apenas por países de rendimento elevado para adultos (7% e 2%, respetivamente) e crianças (12% e 2%, respetivamente). Para testes de casos índice, a maioria dos países utilizou painel génico de sequenciação de próxima geração (NGS) (62%), enquanto para casos não indexados, a maioria baseou-se em variantes específicas por sequenciação Sanger (71%). Este padrão era semelhante tanto em países de rendimento elevado como não elevado; no entanto, alguns países usaram a mesma abordagem de teste tanto para casos índice como não indexados (Figura). As variantes de número de cópia (CNVs) foram avaliadas em 65% dos países, dos quais 86% incorporaram análise CNV em plataformas NGS, enquanto 14% utilizaram amplificação de sonda dependente de ligação multiplex (MLPA) e testes de microarray. Todos os países testados para LDLR, 97% para APOB, e 95% para PCSK9. Em 96% dos países, os relatórios de testes incluíram interpretação de patogenicidade variante (com a maioria a seguir as diretrizes do American College of Medical Genetics and Genomics). Conclusões: A variabilidade generalizada nas práticas de testes genéticos destaca a necessidade crítica de padronização para garantir um diagnóstico de FH eficaz, consistente e comparável a nível global.
- Pharmacogenomic Risk Profiling of Statin Response in Portuguese Familial Hypercholesterolemia and General Population CohortsPublication . Chora, Joana Rita; Grade, M. M.; Antunes, M.; Bourbon, M.Background/Aims: Genetic variants in pharmacogenes involved in statin transport, metabolism, and excretion can increase the risk of adverse effects, particularly statin-associated musculoskeletal symptoms (SAMS). Loss-of-function haplotypes in SLCO1B1 are reliably linked to elevated SAMS risk. Familial hypercholesterolemia (FH), a high cardiovascular disease risk condition, requires lifelong lipid-lowering therapy, often from a young age. However, studies of statin pharmacogenomics in FH patients remain scarce. The Portuguese population, shaped by millennia of admixture, displays a complex genetic background with potential implications for pharmacogenomic diversity. This study aimed to assess the prevalence of high-risk alleles in genes related to statin metabolism and transport, including variants relevant to therapeutic efficacy, in both the general Portuguese population and FH patients. Methods: We analysed 738 adults from the nationally representative e_Cor cohort and 489 clinical FH patients. Genotyping of 13 statin-related single-nucleotide variants (SNV) was conducted using both OpenArrayTM technology and NGS target sequencing. Statin-medicated individuals from both cohorts (N=903) were further analysed for pharmacogenomic risk. Results: Compared to public databases, the frequency of the APOE rs429358 risk allele was significantly lower in the general Portuguese cohort, but significantly higher in statin-medicated individuals and FH patients. Genotype distributions of SLCO1B1, ABCB1, HMGCR, and MTHFR SNVs differed significantly between medicated individuals from the general population and FH patients. Among all participants, 2% had SLCO1B1 poor-function and 22% decreased-function haplotypes; these frequencies were slightly higher in the medicated group (3% and 23%, respectively). Notably, 40% of poor-function and 32% of decreased-function carriers were prescribed a statin dose/type considered high-risk for SAMS. Differences between FH-positive and negative individuals were only observed for APOE rs429358. Conclusion: This study presents a comprehensive overview of statin-related pharmacogenetic variation in the Portuguese population and FH patients. The high prevalence of actionable variants underlines the importance of pharmacogenomic-informed prescribing in high-risk groups. Integrating genetic information into clinical decision-making can optimise statin therapy, mitigate adverse effects, and enhance the effectiveness of personalised lipid-lowering strategies in Portugal.
- Prediction of Genes Associated With Autism Spectrum Disorder Using Sequence And Graph Embedding MethodsPublication . Inácio, João; Vilela, Joana; Marques, Ana Rita; Santos, João Xavier; Rasga, Célia; Vicente, Astrid; Martiniano, HugoIntroduction: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder, characterized by a strong genetic component, heterogeneous phenotypic presentation and complex genetic architecture. [1, 2] Identification of ASD risk genes and biological pathways is key to understand this disorder.[3, 4] Despite the large number of genes associated with ASD, its genetic etiology is still not fully understood. To address this challenge, we developed a machine-learning approach for ASD risk gene prediction. Methods: We developed a Machine Learning–based approach to identify and rank ASD-associated genes. Results and discussion: Prediction of ASD-associated Genes The best model was used to create a ranked list of ASD-associated genes. Using the top decile of the predicted genes, we performed a decile enrichment analysis using Phenotypes from the Human Phenotype Ontology (HPO) database and gene lists for neurodevelopmental disorders and psychiatric disorders unrelated to ASD. Conclusions: We developed a machine learning approach based on sequence and Graph embedding Methods to predict ASD-associated genes. Our approach compares favorably with state-of-the-art approaches in identifying genes targeted by loss-of-function (LOF) mutations in the MSSNG and Simons Simplex Collection cohorts and shows specificity towards ASD-related phenotypes.
- Re-classification of LDLR Variants through High-Throughput Functional Characterisation: Advancing Diagnosis in Familial HypercholesterolaemiaPublication . Chora, Joana Rita; Islam, Mohammad Majharul; Alves, Ana Catarina; Pfisterer, Simon; Bourbon, MafaldaBackground: Familial hypercholesterolaemia (FH) is the most common autosomal disorder of lipid metabolism, affecting approximately 1 in 300 individuals. FH is characterised by markedly elevated plasma cholesterol levels from birth, predisposing to premature atherosclerotic cardiovascular disease. The identification of a pathogenic variant in a causative gene provides a definitive diagnosis and enables cascade screening of family members. However, a substantial proportion of FH variants remain classified as variants of uncertain significance (VUS), creating a critical gap in genetic diagnosis and patient management. Purpose: This study aims to implement a high-throughput pipeline for the functional classification of LDLR variants, thereby enabling their clinical re-interpretation and integration into diagnostic practice. Methods: Selected LDLR variants were divided into two groups: a validation set and a test set. The validation group included 7 variants previously classified as benign/likely benign and 50 variants previously classified as pathogenic/likely pathogenic. The test group comprised 131 VUS with no prior functional assessment. Functional activity was evaluated using an automated analysis platform based on multiplexed high-content imaging to quantify LDL uptake, as described previously (Islam, Tamlander, Hlushchenko, Ripatti, & Pfisterer, 2024). Variant classification followed FH VCEP LDLR-specific guidelines (Chora et al., 2022). Results: In total, 187 LDLR variants were analysed. In the validation group, 44 variants demonstrated completely concordant results with previous classifications, 8 fell within an intermediate "grey zone" (70–90% LDL uptake), and only 5 pathogenic variants were misclassified, yielding a sensitivity of 88.4%, specificity and precision of 100%, and overall accuracy of 78.9%. Among the test group, 51 variants exhibited <70% of wild-type LDL uptake, 41 showed >90% of wild-type uptake, and 39 fell into the intermediate range, requiring additional functional studies. Integrating these findings with other ACMG/AMP evidence codes, 47 variants were considered “hot VUS”, amenable to reclassification. Of these, 9 were reclassified as likely benign and 11 as likely pathogenic. Conclusions: This large-scale functional study of LDLR variants demonstrates the feasibility and clinical utility of integrating high-throughput functional evidence with high accuracy into variant interpretation. The ability to reclassify previously unresolved VUS represents a major step forward in reducing diagnostic uncertainty in FH. The PerMedFH project paves the way for a personalised medicine approach in FH, improving diagnostic precision, and ultimately enhancing patient care and cardiovascular outcomes.
- Truncating APOB Variants Impair LDL Metabolism: Functional Evidence From Binding StudiesPublication . Ferreira, Maria Simões; Larrea-Sebal, Asier; Martín, César; Apellaniz-Ruiz, Maria; Ernaga-Lorea, Ander; Bourbon, Mafalda; Alves, Ana CatarinaFamilial hypercholesterolaemia ( is a condition caused by pathogenic variants in LDLR APOB or PCSK 9 genes, characterised by high levels of LDL cholesterol and premature cardiovascular disease ( APOB variants account for 5 10 of FH cases, most being due to missense variants however, this can be higher than initially estimated Although truncating variants are typically associated with hypocholesterolaemia phenotype, some have been reported in clinical FH patients and can be the cause of diseaseThis study is part of the PerMedFH project and aimed to functionally characterise four nonsense APOB variants in exon 29 identified in patients with a clinical diagnosis of FH, emphasising on their molecular consequences and possible contribution to the FH phenotype. This study is part of the PerMedFH project and aimed to functionally characterise four nonsense APOB variants in exon 29 identified in patients with a clinical diagnosis of FH, emphasising on their molecular consequences and possible contribution to the FH phenotype
- Ultra-portable Nanopore Sequencing With Adaptive Sampling For Clinical Diagnostics: Preliminary Evaluation Using Monogenic Diabetes As a ModelPublication . Vaz, Margarida; Gaspar, Gisela; Bourbon, Mafalda; Dario, PauloNext-generation sequencing is essential in clinical genetics, and Oxford Nanopore technology offers advantages such as portability, rapid analysis, and potential for use outside traditional laboratory environments. This work aimed to evaluate the implementation of the MinION MK1D, operated with a standard laptop, to analyze patients with a targeted 72-gene panel related to monogenic diabetes, using adaptive sampling. Sixteen samples were sequenced, and performance was assessed based on coverage depth and downstream bioinformatic analysis. All samples produced data across the target regions, with an average depth of 2–3×, which limited reliable variant calling. However, interpretable results were still obtained, indicating that with further optimization—such as improved workflow design and enhanced computational resources—Nanopore sequencing could become suitable for decentralized and on-site clinical genetic testing