{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:20:26Z","timestamp":1790716826941,"version":"4.1.0"},"reference-count":98,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). Two forms of the disease are possible, heterozygous (HeFH) and homozygous (HoFH), caused by one or two pathogenic variants, respectively, in the three main genes that are responsible for the autosomal dominant disease: LDLR, APOB and PCSK9 genes. The HeFH is the most common genetic disease in humans, being the prevalence about 1:300. Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. In addition, variants in genes causing other dyslipidemias showing phenotypes overlapping with FH may mimic FH in patients without causative variants (FH-phenocopies; ABCG5, ABCG8, CYP27A1 and LIPA genes) or act as phenotype modifiers in patients with a pathogenic variant in a causative gene. The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. This review aims to report the updates on the genetic and molecular bases of FH with their implication for molecular diagnosis.<\/jats:p>","DOI":"10.3390\/ijms24043224","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T01:56:48Z","timestamp":1675735008000},"page":"3224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0618-7940","authenticated-orcid":false,"given":"Maria Donata","family":"Di Taranto","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Naples, Italy"},{"name":"CEINGE-Biotecnologie avanzate Franco Salvatore, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Fortunato","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Naples, Italy"},{"name":"CEINGE-Biotecnologie avanzate Franco Salvatore, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1093\/eurheartj\/ehu274","article-title":"Homozygous Familial Hypercholesterolaemia: New Insights and Guidance for Clinicians to Improve Detection and Clinical Management. A Position Paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society","volume":"35","author":"Cuchel","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e016461","DOI":"10.1136\/bmjopen-2017-016461","article-title":"Estimating the Prevalence of Heterozygous Familial Hypercholesterolaemia: A Systematic Review and Meta-Analysis","volume":"7","author":"Akioyamen","year":"2017","journal-title":"BMJ Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1161\/CIRCULATIONAHA.119.044795","article-title":"Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis","volume":"141","author":"Hu","year":"2020","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1016\/j.jacc.2020.03.057","article-title":"Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects","volume":"75","author":"Beheshti","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"840797","DOI":"10.3389\/fgene.2022.840797","article-title":"Familial Hypercholesterolemia Prevalence Among Ethnicities-Systematic Review and Meta-Analysis","volume":"13","author":"Emanuelsson","year":"2022","journal-title":"Front. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1093\/eurheartj\/ehy479","article-title":"Why Is Hypercholesterolaemia so Prevalent? A View from Evolutionary Medicine","volume":"40","author":"Laufs","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.jacl.2022.09.006","article-title":"A Mechanism-Based Operational Definition and Classification of Hypercholesterolemia","volume":"16","author":"Civeira","year":"2022","journal-title":"J. Clin. Lipidol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17093","DOI":"10.1038\/nrdp.2017.93","article-title":"Familial Hypercholesterolaemia","volume":"3","author":"Defesche","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.ecl.2022.02.008","article-title":"Lipid and Lipoprotein Metabolism","volume":"51","author":"Feingold","year":"2022","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1056\/NEJM197606172942509","article-title":"Familial Hypercholesterolemia: A Genetic Defect in the Low-Density Lipoprotein Receptor","volume":"294","author":"Brown","year":"1976","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1038\/s41598-020-58734-9","article-title":"Mutation Type Classification and Pathogenicity Assignment of Sixteen Missense Variants Located in the EGF-Precursor Homology Domain of the LDLR","volume":"10","author":"Uribe","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.atherosclerosis.2021.01.008","article-title":"Comparison of the Mutation Spectrum and Association with Pre and Post Treatment Lipid Measures of Children with Heterozygous Familial Hypercholesterolaemia (FH) from Eight European Countries","volume":"319","author":"Futema","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/cge.13826","article-title":"Mutation Spectrum and Polygenic Score in German Patients with Familial Hypercholesterolemia","volume":"98","author":"Rieck","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.atherosclerosissup.2017.07.002","article-title":"LIPIGEN Group Spectrum of Mutations in Italian Patients with Familial Hypercholesterolemia: New Results from the LIPIGEN Study","volume":"29","author":"Pirillo","year":"2017","journal-title":"Atheroscler. Suppl."},{"key":"ref_16","first-page":"8","article-title":"Preliminary Spectrum of Genetic Variants in Familial Hypercholesterolemia in Argentina","volume":"11","year":"2017","journal-title":"J. Clin. Lipidol."},{"key":"ref_17","first-page":"247","article-title":"Familial Hypercholesterolemia in Gran Canaria: Founder Mutation Effect and High Frequency of Diabetes","volume":"33","author":"Tugores","year":"2021","journal-title":"Clin. Investig. Arterioscler"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jacl.2020.03.002","article-title":"A Catalog of the Pathogenic Mutations of LDL Receptor Gene in Japanese Familial Hypercholesterolemia","volume":"14","author":"Tada","year":"2020","journal-title":"J. Clin. Lipidol."},{"key":"ref_19","unstructured":"Adam, M.P., Everman, D.B., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J., Gripp, K.W., and Amemiya, A. (1993). GeneReviews\u00ae, University of Washington."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/joim.13577","article-title":"Genetic and Molecular Architecture of Familial Hypercholesterolemia","volume":"193","author":"Abifadel","year":"2023","journal-title":"J. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.atherosclerosis.2018.06.819","article-title":"Further Evidence of Novel APOB Mutations as a Cause of Familial Hypercholesterolaemia","volume":"277","author":"Alves","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/ng1161","article-title":"Mutations in PCSK9 Cause Autosomal Dominant Hypercholesterolemia","volume":"34","author":"Abifadel","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Alnouri, F., and Santos, R.D. (2022). New Trends and Therapies for Familial Hypercholesterolemia. J. Clin. Med., 11.","DOI":"10.3390\/jcm11226638"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/MOL.0000000000000386","article-title":"Complexity of Mechanisms among Human Proprotein Convertase Subtilisin-Kexin Type 9 Variants","volume":"28","author":"Dron","year":"2017","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"28856","DOI":"10.1074\/jbc.M109.037085","article-title":"Dissection of the Endogenous Cellular Pathways of PCSK9-Induced Low Density Lipoprotein Receptor Degradation: Evidence for an Intracellular Route","volume":"284","author":"Poirier","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.atherosclerosis.2019.08.020","article-title":"The Arg499His Gain-of-Function Mutation in the C-Terminal Domain of PCSK9","volume":"289","author":"Uribe","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/MOL.0000000000000664","article-title":"Autosomal Recessive Hypercholesterolemia: Update for 2020","volume":"31","author":"Arca","year":"2020","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1016\/j.jacc.2016.03.520","article-title":"Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia","volume":"67","author":"Khera","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.jacc.2018.05.044","article-title":"Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel","volume":"72","author":"Sturm","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1177\/2047487317702040","article-title":"Causative Mutations and Premature Cardiovascular Disease in Patients with Heterozygous Familial Hypercholesterolaemia","volume":"24","author":"Rubba","year":"2017","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/cge.14036","article-title":"Genetic Spectrum of Familial Hypercholesterolemia and Correlations with Clinical Expression: Implications for Diagnosis Improvement","volume":"100","author":"Giacobbe","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1515\/cclm-2018-1037","article-title":"Lipid Profile and Genetic Status in a Familial Hypercholesterolemia Pediatric Population: Exploring the LDL\/HDL Ratio","volume":"57","author":"Guardamagna","year":"2019","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.numecd.2021.10.025","article-title":"Association between Causative Mutations and Response to PCSK9 Inhibitor Therapy in Subjects with Familial Hypercholesterolemia: A Single Center Real-World Study","volume":"32","author":"Iannuzzo","year":"2022","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.numecd.2020.02.018","article-title":"Changes in Carotid Stiffness in Patients with Familial Hypercholesterolemia Treated with Evolocumab\u00ae: A Prospective Cohort Study","volume":"30","author":"Gentile","year":"2020","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0140-6736(21)02001-8","article-title":"Worldwide Experience of Homozygous Familial Hypercholesterolaemia: Retrospective Cohort Study","volume":"399","author":"Tromp","year":"2022","journal-title":"Lancet"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Di Taranto, M.D., Giacobbe, C., Buonaiuto, A., Calcaterra, I., Palma, D., Maione, G., Iannuzzo, G., Di Minno, M.N.D., Rubba, P., and Fortunato, G. (2020). A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010219"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"937750","DOI":"10.3389\/fgene.2022.937750","article-title":"Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study","volume":"13","author":"Giammanco","year":"2022","journal-title":"Front. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1097\/MOL.0000000000000853","article-title":"New Algorithms for Treating Homozygous Familial Hypercholesterolemia","volume":"33","author":"Tromp","year":"2022","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1161\/ATVBAHA.120.315204","article-title":"ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL ApoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report","volume":"41","author":"Reeskamp","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1007\/s11883-022-01054-2","article-title":"Bempedoic Acid: For Whom and When","volume":"24","author":"Ruscica","year":"2022","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.atherosclerosissup.2017.07.001","article-title":"LIPIGEN Group Familial Hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)","volume":"29","author":"Averna","year":"2017","journal-title":"Atheroscler. Suppl."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1161\/ATVBAHA.116.308027","article-title":"Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically","volume":"36","author":"Wang","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4313","DOI":"10.1093\/hmg\/ddq352","article-title":"Identification by Whole-Genome Resequencing of Gene Defect Responsible for Severe Hypercholesterolemia","volume":"19","author":"Rios","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1136\/jmedgenet-2014-102405","article-title":"Whole Exome Sequencing of Familial Hypercholesterolaemia Patients Negative for LDLR\/APOB\/PCSK9 Mutations","volume":"51","author":"Futema","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ejhg.2010.94","article-title":"A Fourth Locus for Autosomal Dominant Hypercholesterolemia Maps at 16q22.1","volume":"18","author":"Marduel","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/j.1399-0004.2010.01485.x","article-title":"A Presumptive New Locus for Autosomal Dominant Hypercholesterolemia Mapping to 8q24.22","volume":"79","author":"Cenarro","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/humu.22215","article-title":"Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p.Leu167del Mutation","volume":"34","author":"Marduel","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_49","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_50","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/MOL.0000000000000146","article-title":"The Crucial Roles of Apolipoproteins E and C-III in ApoB Lipoprotein Metabolism in Normolipidemia and Hypertriglyceridemia","volume":"26","author":"Sacks","year":"2015","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.atherosclerosis.2021.05.007","article-title":"APOE Gene Variants in Primary Dyslipidemia","volume":"328","author":"Khalil","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Abou Khalil, Y., Marmontel, O., Ferri\u00e8res, J., Paillard, F., Yelnik, C., Carreau, V., Charri\u00e8re, S., Bruckert, E., Gallo, A., and Giral, P. (2022). APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105792"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/j.jacc.2008.06.050","article-title":"Frequency of Low-Density Lipoprotein Receptor Gene Mutations in Patients with a Clinical Diagnosis of Familial Combined Hyperlipidemia in a Clinical Setting","volume":"52","author":"Civeira","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/978-3-642-35467-0_18","article-title":"Investigation of Single Nucleotide Polymorphisms Associated to Familial Combined Hyperlipidemia with Random Forests","volume":"19","author":"Staiano","year":"2013","journal-title":"Smart Innov. Syst. Technol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.atherosclerosis.2015.06.036","article-title":"Contribution of Mutations in Low Density Lipoprotein Receptor (LDLR) and Lipoprotein Lipase (LPL) Genes to Familial Combined Hyperlipidemia (FCHL): A Reappraisal by Using a Resequencing Approach","volume":"242","author":"Minicocci","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1161\/ATVBAHA.120.314006","article-title":"Delisting STAP1: The Rise and Fall of a Putative Hypercholesterolemia Gene","volume":"40","author":"Hegele","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"574474","DOI":"10.3389\/fgene.2020.574474","article-title":"Genetics of Familial Hypercholesterolemia: New Insights","volume":"11","author":"Vrablik","year":"2020","journal-title":"Front. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-981-15-6082-8_8","article-title":"Recent Advances in the Critical Role of the Sterol Efflux Transporters ABCG5\/G8 in Health and Disease","volume":"1276","author":"Wang","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jacl.2020.01.007","article-title":"ABCG5 and ABCG8 Genetic Variants in Familial Hypercholesterolemia","volume":"14","author":"Reeskamp","year":"2020","journal-title":"J. Clin. Lipidol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1111\/joim.13277","article-title":"Cerebrotendinous Xanthomatosis without Neurological Involvement","volume":"290","author":"Stelten","year":"2021","journal-title":"J. Intern. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1007\/s11011-016-9841-y","article-title":"Cerebrotendinous Xanthomatosis, a Metabolic Disease with Different Neurological Signs: Two Case Reports","volume":"31","author":"Gelzo","year":"2016","journal-title":"Metab. Brain Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.atherosclerosis.2018.06.009","article-title":"Unusual Genetic Variants Associated with Hypercholesterolemia in Argentina","volume":"277","author":"Corral","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1399-0004.2011.01793.x","article-title":"Extreme Xanthomatosis in Patients with Both Familial Hypercholesterolemia and Cerebrotendinous Xanthomatosis","volume":"81","author":"Huijgen","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Mashima, R., and Takada, S. (2022). Lysosomal Acid Lipase Deficiency: Genetics, Screening, and Preclinical Study. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415549"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"936121","DOI":"10.3389\/fgene.2022.936121","article-title":"Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program","volume":"13","author":"Sustar","year":"2022","journal-title":"Front. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1016\/j.jacl.2018.08.006","article-title":"Oligogenic Familial Hypercholesterolemia, LDL Cholesterol, and Coronary Artery Disease","volume":"12","author":"Tada","year":"2018","journal-title":"J. Clin. Lipidol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.atherosclerosis.2011.08.004","article-title":"A Novel Type of Familial Hypercholesterolemia: Double Heterozygous Mutations in LDL Receptor and LDL Receptor Adaptor Protein 1 Gene","volume":"219","author":"Tada","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Ghaleb, Y., Elbitar, S., Philippi, A., El Khoury, P., Azar, Y., Andrianirina, M., Loste, A., Abou-Khalil, Y., Nicolas, G., and Le Borgne, M. (2022). Whole Exome\/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia. Metabolites, 12.","DOI":"10.3390\/metabo12030262"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"551","DOI":"10.5551\/jat.58909","article-title":"A Resuscitated Case of Acute Myocardial Infarction with Both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the PCSK9 and ABCG5 Genes and Type I CD36 Deficiency","volume":"29","author":"Nishikawa","year":"2022","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/humu.21660","article-title":"Genetic Variation in APOB, PCSK9, and ANGPTL3 in Carriers of Pathogenic Autosomal Dominant Hypercholesterolemic Mutations with Unexpected Low LDL-Cl Levels","volume":"33","author":"Huijgen","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1194\/jlr.M092049","article-title":"In Search of a Genetic Explanation for LDLc Variability in an FH Family: Common SNPs and a Rare Mutation in MTTP Explain Only Part of LDL Variability in an FH Family","volume":"60","author":"Winther","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"942772","DOI":"10.3389\/fcvm.2022.942772","article-title":"Case Report: Unusual Coexistence between Familial Hypercholesterolemia and Familial Hypobetalipoproteinemia","volume":"9","author":"Sasaki","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/j.jacl.2016.08.011","article-title":"Familial Combined Hyperlipidemia and Hyperlipoprotein(a) as Phenotypic Mimics of Familial Hypercholesterolemia: Frequencies, Associations and Predictions","volume":"10","author":"Ellis","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1093\/eurheartj\/ehac361","article-title":"Lipoprotein(a) in Atherosclerotic Cardiovascular Disease and Aortic Stenosis: A European Atherosclerosis Society Consensus Statement","volume":"43","author":"Kronenberg","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.atherosclerosis.2021.08.009","article-title":"Lipoprotein(a) in Hereditary Hypercholesterolemia: Influence of the Genetic Cause, Defective Gene and Type of Mutation","volume":"349","author":"Cenarro","year":"2022","journal-title":"Atherosclerosis"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.atherosclerosis.2022.04.021","article-title":"Lipoprotein(a) and Family History for Cardiovascular Disease in Paediatric Patients: A New Frontier in Cardiovascular Risk Stratification. Data from the LIPIGEN Paediatric Group","volume":"349","author":"Pederiva","year":"2022","journal-title":"Atherosclerosis"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s11883-022-01002-0","article-title":"Lipoprotein(a) as Part of the Diagnosis of Clinical Familial Hypercholesterolemia","volume":"24","author":"Langsted","year":"2022","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/S0140-6736(12)62127-8","article-title":"Use of Low-Density Lipoprotein Cholesterol Gene Score to Distinguish Patients with Polygenic and Monogenic Familial Hypercholesterolaemia: A Case-Control Study","volume":"381","author":"Talmud","year":"2013","journal-title":"Lancet"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1373\/clinchem.2014.231365","article-title":"Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries","volume":"61","author":"Futema","year":"2015","journal-title":"Clin. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4330","DOI":"10.1038\/s41467-019-12026-7","article-title":"The Transferability of Lipid Loci across African, Asian and European Cohorts","volume":"10","author":"Kuchenbaecker","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Vanhoye, X., Bardel, C., Rimbert, A., Moulin, P., Rollat-Farnier, P.-A., Muntaner, M., Marmontel, O., Dumont, S., Charri\u00e8re, S., and Corn\u00e9lis, F. (2022). A New 165-SNP Low-Density Lipoprotein Cholesterol Polygenic Risk Score Based on next Generation Sequencing Outperforms Previously Published Scores in Routine Diagnostics of Familial Hypercholesterolemia. Transl. Res., S1931-5244(22)00281-X.","DOI":"10.1016\/j.trsl.2022.12.002"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1038\/s41467-018-05747-8","article-title":"Deep-Coverage Whole Genome Sequences and Blood Lipids among 16,324 Individuals","volume":"9","author":"Natarajan","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1161\/CIRCGEN.120.002919","article-title":"Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia","volume":"13","author":"Trinder","year":"2020","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Rutkowska, L., Pinkier, I., Sa\u0142aci\u0144ska, K., K\u0119pczy\u0144ski, \u0141., Salachna, D., Lewek, J., Banach, M., Matusik, P., Starostecka, E., and Lewi\u0144ski, A. (2022). Identification of New Copy Number Variation and the Evaluation of a CNV Detection Tool for NGS Panel Data in Polish Familial Hypercholesterolemia Patients. Genes, 13.","DOI":"10.3390\/genes13081424"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.cjca.2018.07.479","article-title":"Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia","volume":"34","author":"Iacocca","year":"2018","journal-title":"Can. J. Cardiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1038\/s41467-022-33510-7","article-title":"Whole Genome Sequence Analysis of Blood Lipid Levels in >66,000 Individuals","volume":"13","author":"Selvaraj","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_87","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_88","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/gim.2017.151","article-title":"Analysis of Publicly Available LDLR, APOB, and PCSK9 Variants Associated with Familial Hypercholesterolemia: Application of ACMG Guidelines and Implications for Familial Hypercholesterolemia Diagnosis","volume":"20","author":"Chora","year":"2018","journal-title":"Genet. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.gim.2021.09.012","article-title":"The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel Consensus Guidelines for LDLR Variant Classification","volume":"24","author":"Chora","year":"2022","journal-title":"Genet. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.numecd.2015.06.007","article-title":"Functional Characterization of Mutant Genes Associated with Autosomal Dominant Familial Hypercholesterolemia: Integration and Evolution of Genetic Diagnosis","volume":"25","author":"Fortunato","year":"2015","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1002\/humu.23634","article-title":"ClinVar Database of Global Familial Hypercholesterolemia-Associated DNA Variants","volume":"39","author":"Iacocca","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"147084","DOI":"10.1016\/j.gene.2022.147084","article-title":"LDLR Missense Variants Disturb Structural Conformation and LDLR Activity in T-Lymphocytes of Familial Hypercholesterolemia Patients","volume":"853","author":"Barbosa","year":"2022","journal-title":"Gene"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1194\/jlr.D017772","article-title":"An Improved Method on Stimulated T-Lymphocytes to Functionally Characterize Novel and Known LDLR Mutations","volume":"52","author":"Romano","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"15282","DOI":"10.1038\/s41598-017-15543-x","article-title":"Identification and in Vitro Characterization of Two New PCSK9 Gain of Function Variants Found in Patients with Familial Hypercholesterolemia","volume":"7","author":"Giacobbe","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e175","DOI":"10.1515\/cclm-2014-0144","article-title":"The Novel Variant p.Ser465Leu in the PCSK9 Gene Does Not Account for the Decreased LDLR Activity in Members of a FH Family","volume":"52","author":"Ruotolo","year":"2014","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"100166","DOI":"10.1016\/j.crmeth.2022.100166","article-title":"Multiparametric Platform for Profiling Lipid Trafficking in Human Leukocytes","volume":"2","author":"Pfisterer","year":"2022","journal-title":"Cell Rep. Methods"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.jacbts.2021.08.009","article-title":"MLb-LDLr: A Machine Learning Model for Predicting the Pathogenicity of LDLr Missense Variants","volume":"6","author":"Uribe","year":"2021","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_98","first-page":"954598","article-title":"Statistical and Computational Methods for Genetic Diseases: An Overview","volume":"2015","author":"Camastra","year":"2015","journal-title":"Comput. Math. Methods Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3224\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:25:56Z","timestamp":1760120756000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,6]]},"references-count":98,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043224"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043224","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,6]]}}}