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- Application of a Pilot Screening Program for Familial Hypercholesterolemia in a High-Complexity Hospital CenterPublication . Radojkovic, Claudia; Honorato, Paula; Portiño, René; Martínez, Catalina; Saez, Katia; Bourbon, Mafalda; Muñoz, Isabel; Alvarado, Cristóbal; Guzmán, Enrique; Bustos, Paulina; Alonso, Rodrigo; Sánchez, AndreaOne of the current challenges is the early identification of patients with Familial Hypercholesterolemia (FH) through clinical diagnosis and genetic analysis to initiate treatment and prevent the development of atherosclerotic disease. Aim: To describe the results of a pilot program for opportunistic screening of Familial Hypercholesterolemia index cases in a highly complex hospital laboratory. Materials and methods: Retrospective cross-sectional convenience recruitment study. Search for patients with clinical suspicion of FH was conducted by analyzing the lipid profile of users from the Las Higueras Hospital of Talcahuano, between 2019 and 2021. Patients were selected and stratified according to LDL-C concentrations using the Dutch Lipid Clinic Network (DLCN) Criteria. Patients with a DLCN score >6 were selected as candidates for genetic diagnosis. Results: 36,804 lipid profiles were obtained, of which 19,021 corresponded to a unique lipid profile per patient. After applying the exclusion criteria, 98 patients suspected of FH. According to the DLCN criteria, 5 patients were stratified with a definitive clinical diagnosis (DLCN ≥8) and 4 with a probable diagnosis of FH (DLCN 6-7). In 4 of the 6 patients who were contacted, 3 genetic variants associated with FH were identified. Conclusion: This work corresponds to the first report on the application of an FH screening program in a highly complex hospital center in Chile and allowed the definitive diagnosis of pediatric and adult patients with FH. These results demonstrate the importance of implementing an opportunistic screening program and performing genetic analysis for FH variants to a definitive diagnosis.
- UBR5 Loss-of-function Variants In Autism Spectrum Disorder And Intellectual Disability: Case Series And Review Of The LiteraturePublication . Reuter, Miriam S.; Salazar, Nelson Bautista; Howe, Jennifer L.; Hoang, Ny; Sarikaya, Ege; Selvanayagam, Thanuja; Mendes de Aquino, Marla; Vicente, Astrid M.; Oliveira, Guiomar; Freitag, Christine M.; Thiruvahindrapuram, Bhooma; Trost, Brett; Scherer, Stephen W.UBR5 encodes an E3 ubiquitin-protein ligase which targets distinct N-terminal residues of proteins for degradation. Heterozygous loss-of-function variants were reported in patients with Autism Spectrum Disorder (ASD) and developmental delay, and recently in a cohort of individuals with neurodevelopmental disorders and variable other features. Here, we report three unrelated individuals with de novo loss-of-function variants in UBR5, presenting with ASD and intellectual disability. We review the literature for other de novo predicted loss-of-function variants in probands with ASD or developmental delay (in total n = 11 variants), providing further evidence that UBR5 haploinsufficiency is associated with ASD and atypical neurodevelopmental trajectories, including developmental delay and intellectual disability.
- Editorial: Empowering Early Career Researchers In Psychiatry: Advancing Autism ResearchPublication . Caruso, Angela; Rasga, Célia; Fulceri, Francesca; Scattoni, Maria Luisa; Micai, MartinaNo abstract available
- Exploring literacy and knowledge gaps and disparities in genetics and oncogenomics among cancer patients and the general population: A Scoping ReviewPublication . Nikitara, Katerina; Cardoso, Maria Luis; Vicente, Astrid Moura; Rasga, Célia Maria Batalha Silva; De Angelis, Roberta; Morel, Zeina Chamoun; De Nicolo, Arcangela; Nomikou, Maria; Karamanidou, Christina; Kakalou, ChristineBackground: Genetic and genomic literacy is pivotal in empowering cancer patients and citizens to navigate the complexities of omics sciences, resolve misconceptions surrounding clinical research and genetic/genomic testing, and make informed decisions about their health. In a fast-evolving scenario where routine testing has become widespread in healthcare, this scoping review sought to pinpoint existing gaps in literacy and understanding among cancer patients and the general public regarding genetics and genomics. Methods: Adhering to the PRISMA framework, the review included 43 studies published between January 2018 and June 2024, which evaluated the understanding of genetics and genomics among cancer patients, caregivers, and citizens. Results: Although the selected studies had significant heterogeneity in populations and evaluation tools, our findings indicate inadequate literacy levels, with citizens displaying lower proficiency than cancer patients and caregivers. This review highlighted consistent knowledge gaps in understanding the genetic and genomic underpinnings of diseases, encompassing misconceptions about mutation types and inheritance patterns, limited awareness of available genetic testing options, and difficulties in interpreting test results. Ethical and privacy concerns and the psychological impact of genetic testing were also common, highlighting the imperative need for effective communication between healthcare providers and patients. Conclusions: Given the dynamic nature of genomic science, the review underscores the need for continuously evolving educational programs tailored to diverse populations. Our findings could guide the development of educational resources addressed explicitly to cancer patients, caregivers, and the lay public.
- Proposal of a Familial Hypercholesterolemia Pediatric Diagnostic Score (FH-PeDS)Publication . Kafol, Jan; Miranda, Beatriz; Sikonja, Rok; Sikonja, Jaka; Wiegman, Albert; Medeiros, Ana Margarida; Alves, Ana Catarina; Freiberger, Tomas; Hutten, Barbara A.; Mlinaric, Matej; Battelino, Tadej; Humphries, Steve E.; Bourbon, Mafalda; Groselj, UrhBackground and aims: Familial hypercholesterolemia (FH) significantly increases cardiovascular risk from childhood yet remains widely underdiagnosed. This cross-sectional study aimed to evaluate existing pediatric FH diagnostic criteria in real-world cohorts and to develop two novel diagnostic tools: a semi-quantitative scoring system (FH-PeDS) and a machine learning model (ML-FH-PeDS) to enhance early FH detection. Methods: Five established FH diagnostic criteria were assesed (Dutch Lipid Clinics Network [DLCN], Simon Broome, EAS, Simplified Canadian, and Japanese Atherosclerosis Society) in Slovenian (N=1,360) and Portuguese (N=340) pediatric hypercholesterolemia cohorts, using FH-causing variants as the reference standard. FH-PeDS was developed from the Slovenian cohort, and ML-FH-PeDS was trained and tested using a 60%/40% split before external validation in the Portuguese cohort. Results: Only 47.4% of genetically confirmed FH cases were identified by all established criteria, while 10.9% were missed entirely. FH-PeDS outperformed DLCN in the combined cohort (AUC 0.897 vs. 0.857; p<0.01). ML-FH-PeDS showed superior predictive power (AUC 0.932 in training, 0.904 in testing vs. 0.852 for DLCN; p<0.01) and performed best as a confirmatory test in the testing subgroup (39.7% sensitivity, 87.7% PPV at 98% specificity). In the Portuguese cohort, ML-FH-PeDS maintained strong predictive performance (AUC 0.867 vs. 0.815 for DLCN; p<0.01) despite population differences. Conclusions: Current FH diagnostic criteria perform suboptimally in children. FH-PeDS and ML-FH-PeDS provide tools to improve FH detection, particularly where genetic testing is limited. They also help guide genetic testing decisions for hypercholesterolemic children. By enabling earlier diagnosis and intervention, these tools may reduce long-term cardiovascular risk and improve outcomes.
- Functional characterization of 16 variants found in the LDL receptor genePublication . Konečná, Kateřina; Přerovská, Tereza; Loja, Tomáš; Fajkusová, Lenka; Koutná, Jana; Kramárek, Michal; Alves, Ana Catarina; Bourbon, Mafalda; Freiberger, Tomáš; Tichý, LukášFamilial hypercholesterolemia (FH) is a disorder of cholesterol metabolism characterized by elevated LDL-cholesterol levels. The most common cause of FH is pathogenic variants in the LDL receptor (LDLR) gene. To shed light on the functional impact of selected LDLR variants, we functionally characterized 16 LDLR genetic variants alongside 10 control variants. We performed in vitro assays based on transient expression of WT and mutant LDLRs in LDLR-deficient Chinese hamster ovary cells. We used flow cytometry to analyze the relative amount of LDLRs expressed on the cell surface and the relative amount of internalized LDL. In addition, we analyzed the expression and maturation of LDLR protein by Western blotting. Of the 16 studied variants, two variants (p.(Asn272Thr) and p.(Arg574Leu)) did not exhibit a defect in LDLR function, one variant (p.(Ala540Thr)) exhibited a defect in LDL binding and/or internalization despite normal LDLR cell surface expression, and the remaining 13 variants had a detrimental effect on both LDLR cell surface expression and LDL internalization. The information presented in this study contributes to the clinical classification of LDLR variants and a more precise diagnosis of FH patients, highlighting the type of defect each variant produces.
- The Functional Landscape Of Coding Variation In The Familial Hypercholesterolemia Gene LDLRPublication . Tabet, Daniel R.; Coté, Atina G.; Lancaster, Megan C.; Weile, Jochen; Rayhan, Ashyad; Fotiadou, Iosifina; Kishore, Nishka; Li, Roujia; Kuang, Da; Knapp, Jennifer J.; Carrero, Carmela Serio; Taverniti, Olivia; Axakova, Anna; Castelli, Jack M. P.; Islam, Mohammad Majharul; Sowlati-Hashjin, Shahin; Gandhi, Aanshi; Maaieh, Ranim; Garton, Michael; Matreyek, Kenneth; Fowler, Douglas M.; Bourbon, Mafalda; Pfisterer, Simon G.; Glazer, Andrew M.; Kroncke, Brett M.; Parikh, Victoria N.; Ashley, Euan A.; Knowles, Joshua W.; Claussnitzer, Melina; Cirulli, Elizabeth T.; Hegele, Robert A.; Roden, Dan M.; MacRae, Calum A.; Roth, Frederick P.Variants in the familial hypercholesterolemia gene -the most important genetic driver of cardiovascular disease-can raise circulating low-density lipoprotein (LDL) cholesterol concentrations and increase the risk of premature atherosclerosis. Definitive classifications are lacking for nearly half of clinically encountered missense variants, limiting interventions that reduce disease burden. Here, we tested the impact of ~17,000 (nearly all possible) missense coding variants on both LDLR cell-surface abundance and LDL uptake, yielding sequence-function maps that recapitulate known biochemistry, offer functional insights, and provide evidence for interpreting clinical variants. Functional scores correlated with hyperlipidemia phenotypes in prospective human cohorts and augmented polygenic scores to improve risk inference, highlighting the potential of this resource to accelerate familial hypercholesterolemia diagnosis and improve patient outcomes.
- Sitosterolemia In iberoamerican countries: 16 new cases and phenotype genotype analysisPublication . Alves, Ana Catarina; Chora, Joana Rita; Miranda, Beatriz; Medeiros, Ana Margarida; Graça, Rafael; Bañares, Virginia G.; Araujo, Maria Beatriz; Vilagut, Ferrán Trías; Soler, Cristina; Meavilla, Silvia; Toledo, Maria J. Benitez; Volpe, Camila Garcia; Reyes, Ximena; Dell'Oca, Nicolás; Martins, Paula; Marado, Diana; Vilarinho, Laura; Dias, Aureliano Jorge; Ferreira, Ana Cristina; Padeira, Gonçalo; Casañas, Marta; Alegre-González, Diana; Lozano, José Mosquera; Aguiar, Patrício; Gonçalves, Filipa Sousa; Ernaga, Ander; Apellaniz-Ruiz, Maria; Rubi, Rodrigo; Figueroa, Nahún Muñoz; Vasquez, Norma Alejandra; Valdivielso, Pedro; Bourbon, Mafalda; ElsevierBackground: Sitosterolemia is a rare autosomal recessive lipid disorder caused by biallelic pathogenic variants in ABCG5 or ABCG8 genes. It is characterized by elevated plasma plant sterol concentrations, xanthomas, and an increased risk of premature cardiovascular disease. As happens with familial hypercholesterolemia (FH), sitosterolemia is subdiagnosed and is frequently confounded with FH, resulting in inappropriate management. This study aims to describe newly identified cases across Iberoamerican countries and to highlight the need for improved diagnostic strategies. Methods: We report 16 cases of molecularly confirmed sitosterolemia from 5 Iberoamerican countries (Argentina, Mexico, Portugal, Spain, and Uruguay), including 12 index cases and 4 relatives identified by cascade screening. Clinical, biochemical, and molecular data were collected and analyzed. β-sitosterol levels were measured when possible, and variant classification followed American College of Medical Genetics and Genomics (ACMG) guidelines with disease-specific adaptations. Results: Fifteen individuals had biallelic variants in ABCG8 and 1 had a homozygous frameshift variant in ABCG5. Ten distinct ABCG8 variants were identified, including 7 nonsense and 3 missense variants. Xanthomas were observed in 56% of cases. Most cases were initially diagnosed as FH, with a diagnostic delay of up to 30 years. Treatment with ezetimibe, alone or combined with statins, led to biochemical and clinical improvement, including xanthoma regression in some cases. Conclusion: Sitosterolemia remains underdiagnosed due to lack of systematic screening and clinical overlap with FH. Our findings highlight the importance of including ABCG5/8 in genetic testing panels and of recognizing clinical clues for early diagnosis, enabling targeted treatment and prevention of adverse outcomes. Adapted ACMG variant classification improves interpretability for ABCG5/8-related sitosterolemia.
- Neurometabolic profiles of autism spectrum disorder patients with genetic variants in specific neurotransmission and synaptic genesPublication . Vilela, Joana; Pereira, Andreia C.; Violante, Inês R.; Mouga, Susana; Rasga, Célia; Santos, João Xavier; Martiniano, Hugo; Marques, Ana Rita; Oliveira, Guiomar; Castelo-Branco, Miguel; Vicente, Astrid MouraAutism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impaired social interaction, and restricted and repetitive patterns of behavior. ASD presents as a clinical spectrum, with variable levels of severity and multiple co-occurring conditions. The etiology of ASD may involve hundreds of genes and there is evidence that neurotransmitter and synaptic (NS) pathways are implicated. Proton Magnetic Resonance Spectroscopy (H-MRS) has made it possible to study the concentration of brain neurometabolites and compare their levels in the brains of ASD and control individuals. We integrated genetic variants in NS genes with H-MRS analysis, and identified 12 predicted damaging variants (PDVs) in 12 NS genes in 10 ASD individuals, most mapping to genes involved in Gamma-aminobutyric acid (GABA) and glutamate pathways. Total creatine (tCr) and total N-acetyl aspartate (tNAA), markers of bioenergetics and neuronal metabolism, respectively, were lower in ASD patients with genetic alterations in NS genes compared to a control group without ASD. We conclude that PDVs in NS genes that are important for the regulation of glutamate or involved in GABAergic functions are associated with neurometabolic alterations, and that dysfunction in glutamatergic and/or GABAergic pathways may be implicated as these pathways are linked to the metabolic measures altered in cases.
- The current stage of Italy in the implementation of genomics into the National Healthcare System: an application of the B1MG maturity level modelPublication . Baccolini, Valentina; Pitini, Erica; Galeone, Daniela; Marzuillo, Carolina; Cicchetti, Americo; Arca, Marcello; Vicente, Astrid M.; Boccia, Stefania; Villari, PaoloIntroduction: Genomics holds significant promise for prevention and clinical care yet integrating it into the national healthcare system (NHS) requires considerable system-wide changes. This study assessed the current stage of Italy in the use of genomics, to map critical areas for improvement and contribute to a strategic plan. Methods: A total of 18 experts rated individually the level of maturity of the Italian NHS on a scale from 1 (lowest) to 5 (highest) using the B1MG Maturity Level Model tool. This instrument is an European matrix of 49 indicators grouped into eight domains: governance, economic aspects, ethics and legislation, public awareness, workforce skills, clinical organization, clinical guidelines, and data infrastructure. Consensus procedures were performed within each domain to finally agree on one maturity level per indicator. Results: Despite a few national initiatives, Italy shows a local level of implementation in most indicators. Genomic medicine is considered a priority, but still lacks an updated strategy and investment plans. A higher maturity is reached for ethical and legal aspects, but there is a strong need to invest in workforce training, citizen engagement and literacy, and large-scale adoption of tools and novel technologies. Infrastructures and guidelines to improve data storage, management, analysis, interpretation, and sharing are not yet widespread available. Discussion: Italy is at the beginning of its journey towards a sustainable implementation of genomics. An updated national strategy with coordinated actions and investment plans is needed to make progress in key areas, including personnel education, public engagement, technical infrastructure, and clinical organization.