{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:11:05Z","timestamp":1760058665001,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sanofi-Aventis Espa\u00f1a SA"},{"name":"Amgen Espa\u00f1a SA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction and Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipid metabolism that is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and a high risk of atherosclerotic cardiovascular disease. Familial hypercholesterolemia is typically caused by mutations in the LDL receptor gene (LDLR), although other alterations may be found. The aim of this study was to perform a genetic study on a population identified through a new population-based diagnostic screen program for FH. Methods: Genetic variants in LDLR, apolipoprotein B (APOB), apolipoprotein E (APOE), proprotein convertase subtilisin\/kexin type 9 (PCSK9), signal transducing Adaptor Family Member 1 (STAP1), low density lipoprotein receptor adaptor protein 1 (LDLRAP1) and lipase A, and lysosomal acid type lipase A (LIPA), as well as a genetic risk score, were evaluated in 84 individuals with a clinical diagnosis of FH based on the Dutch Lipid Clinics Network criteria (DLCN \u2265 6). These individuals were selected from a cohort of 752 patients with an abnormal lipid profile, obtained by screening existing centralized analytics. Results: A clinical diagnosis of FH was established in 17.9% of the patients evaluated, with mean LDL-C levels of 305.7 mg\/dL (95% CI 250.4\u2013360.9). Genetic variants were detected in 70.2% of these patients, with 50 different mutations identified, mainly in the LDLR. The most frequent pathogenic variants were c.1342C&gt;T and c.313+1G&gt;C. Null variants exhibited a more severe phenotype, and the risk score indicates that patients carrying genetic alterations have a 42% higher risk of developing cardiovascular disease. Conclusions: A high rate of genetic alterations was detected in patients with severe FH. In most cases, the phenotypic findings did not predict the genetic results, which provide important information regarding the cardiovascular risk of patients.<\/jats:p>","DOI":"10.3390\/jcm14082780","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T20:05:56Z","timestamp":1744920356000},"page":"2780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Screening Approach for Familial Hypercholesterolemia: A Genetic Study on Patients Detected Using Preexisting Centralized Analytics"],"prefix":"10.3390","volume":"14","author":[{"given":"Joaqu\u00edn","family":"S\u00e1nchez-Prieto","sequence":"first","affiliation":[{"name":"Department of Cardiology, Toledo University Hospital, 45005 Toledo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Sabatel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Toledo University Hospital, 45005 Toledo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F\u00e1tima","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Toledo University Hospital, 45005 Toledo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel A.","family":"Arias","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Toledo University Hospital, 45005 Toledo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Rodr\u00edguez-Padial","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Toledo University Hospital, 45005 Toledo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1126\/science.3513311","article-title":"A receptor-mediated pathway for cholesterol homeostasis","volume":"232","author":"Brown","year":"1986","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e421","DOI":"10.1093\/aje\/kwh237","article-title":"Familial hypercholesterolemia and coronary heart disease: A HuGE association review","volume":"160","author":"Austin","year":"2004","journal-title":"Am. J. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2004","DOI":"10.1161\/ATVBAHA.116.307514","article-title":"Coronary heart disease, peripheral arterial disease, and stroke in familial hypercholesterolaemia: Insights from the SAFEHEART registry (Spanish familial hypercholesterolaemia cohort study)","volume":"36","author":"Alonso","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.3310\/hta4290","article-title":"Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: A systematic review and cost-effectiveness analysis","volume":"4","author":"Marks","year":"2000","journal-title":"Health Technol. Assess."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.recesp.2019.10.013","article-title":"Incidence of Cardiovascular Events and Changes in the Estimated Risk and Treatment of Familial Hypercholesterolemia: The SAFEHEART Registry","volume":"73","author":"Alonso","year":"2020","journal-title":"Rev. Espa\u00f1ola Cardiol. (Engl. Ed.)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1016\/j.jacc.2019.02.059","article-title":"Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction","volume":"73","author":"Singh","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.aprim.2013.12.015","article-title":"Diagn\u00f3stico y tratamiento de la hiper-colesterolemia familiar en Espa\u00f1a. Documento de consenso","volume":"47","author":"Mata","year":"2015","journal-title":"Aten Primaria."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3478","DOI":"10.1093\/eurheartj\/eht273","article-title":"Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society","volume":"34","author":"Nordestgaard","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_9","first-page":"4758","article-title":"Corrigendum to Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication","volume":"99","author":"Benn","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"a1095","DOI":"10.1136\/bmj.a1095","article-title":"Guideline Development Group. Familial hypercholesterolemia: Summary of NICE guidance","volume":"337","author":"Wierzbicki","year":"2008","journal-title":"BMJ"},{"key":"ref_11","unstructured":"World Health Organization (1999). Familial Hypercholesterolemia: Report of a Second WHO Consultation, World Health Organisation, Human Genetics programme, Division of Non-communicable Diseases. WHO Publication No. WHO7HGN\/FH\/CONS\/99.2."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.jacc.2018.05.044","article-title":"Clinical Genetic Testing for Familial Hypercholesterolemia","volume":"72","author":"Sturm","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_13","unstructured":"Rosenson, R.S., de Ferranti, S.D., and Durrington, M.P.H.P. (2014). Inherited Disorders of LDL-Cholesterol Metabolism, UpToDate."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sabatel-P\u00e9rez, F., S\u00e1nchez-Prieto, J., Becerra-Mu\u00f1oz, V.M., Alonso-Briales, J.H., Mata, P., and Rodr\u00edguez-Padial, L. (2021). Improving Familial Hypercholesterolemia Index Case Detection: Sequential Active Screening from Centralized Analytical Data. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040749"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1016\/j.jacc.2017.08.009","article-title":"Genetically Confirmed Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome","volume":"70","author":"Castillo","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ijcard.2013.11.025","article-title":"Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation","volume":"171","author":"Watts","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.atherosclerosis.2013.08.035","article-title":"New EAS Consensus Statement on FH: Improving the care of FH patients","volume":"231","author":"Stock","year":"2013","journal-title":"Atherosclerosis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1194\/jlr.P055699","article-title":"Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France","volume":"57","author":"Wintjens","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1161\/CIRCRESAHA.115.304660","article-title":"Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia","volume":"115","author":"Fouchier","year":"2014","journal-title":"Circ. Res."},{"key":"ref_21","first-page":"287","article-title":"Genetic Risk Stratification: A Paradigm Shift in Prevention of Coronary Artery Disease","volume":"6","author":"Roberts","year":"2021","journal-title":"J. Am. Coll. Cardiol. Basic Trans. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1161\/CIRCGENETICS.116.001522","article-title":"Clinical Utility of Multimarker Genetic Risk Scores for Prediction of Incident Coronary Heart Disease: A Cohort Study Among Over 51 Thousand Individuals of European Ancestry","volume":"9","author":"Iribarren","year":"2016","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_23","first-page":"128","article-title":"Indications of PCSK9 inhibitors in clinical practice. Recommendations of the Spanish Sociey of Arteriosclerosis (SEA)","volume":"31","author":"Ascaso","year":"2019","journal-title":"Clin. Investig. Arterioscler."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.atherosclerosis.2017.04.002","article-title":"Mutational Analysis and Genotype-Phenotype Relation in Familial Hypercholesterolemia: The SAFEHEART Registry","volume":"262","author":"Bourbon","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e55","DOI":"10.1016\/j.ejim.2011.01.003","article-title":"Spectrum of LDLR Gene Mutations, Including a Novel Mutation Causing Familial Hypercholesterolaemia, in North-Western Greece","volume":"22","author":"Diakou","year":"2011","journal-title":"Eur. J. Intern. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13276","DOI":"10.1016\/S0021-9258(18)37701-9","article-title":"Transport-deficient mutations in the low density lipoprotein receptor: Alterations in the cysteine rich and cysteine-poor regions of the protein block intracellular transport","volume":"263","author":"Esser","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0021-9150(99)00158-6","article-title":"Spectrum of LDL Receptor Gene Mutations in Denmark: Implications for Molecular Diagnostic Strategy in Heterozygous Familial Hypercholesterolemia","volume":"146","author":"Jensen","year":"1999","journal-title":"Atherosclerosis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e316","DOI":"10.1038\/gim.2015.71","article-title":"Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: Considerations for genetic diagnosis improvement","volume":"18","author":"Medeiros","year":"2016","journal-title":"Genet. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e387","DOI":"10.1111\/j.1469-1809.2012.00724.x","article-title":"Low density lipoprotein receptor gene familial hypercholesterolemia variant database: Update and pathological assessment","volume":"76","author":"Usifo","year":"2012","journal-title":"Ann. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1161\/01.CIR.92.3.290","article-title":"Coronary artery disease in heterozygous familial hypercholesterolaemia patients with the same LDL receptor gene mutation","volume":"92","author":"Ferrieres","year":"1995","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/j.1365-2796.2004.01405.x","article-title":"The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: Data in 2400 patients","volume":"256","author":"Jansen","year":"2004","journal-title":"J. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.atherosclerosis.2007.12.024","article-title":"Cardiovascular Disease in Familial Hypercholesterolaemia: Influence of Low-Density Lipoprotein Receptor Mutation Type and Classic Risk Factors","volume":"200","author":"Alonso","year":"2008","journal-title":"Atherosclerosis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/eurheartj\/ehz455","article-title":"2019 ESC\/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk","volume":"41","author":"Mach","year":"2020","journal-title":"Eur. Heart J."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/8\/2780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:16:33Z","timestamp":1760030193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/8\/2780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,17]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["jcm14082780"],"URL":"https:\/\/doi.org\/10.3390\/jcm14082780","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2025,4,17]]}}}