{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:13:13Z","timestamp":1783573993673,"version":"3.55.0"},"reference-count":84,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Familial hypercholesterolemia (FH) and familial hypertriglyceridemia (FHTG) represent a spectrum of inherited conditions with profoundly different etiologies, risk profiles, and therapeutic implications. Despite decades of clinical experience, their formal diagnostic definitions remain rooted in frameworks developed before the genomic era (the Dutch Lipid Clinic Network (DLCN) score), leading to substantial gaps in diagnostic accuracy. This review traces the historical evolution of diagnostic criteria for FH and FHTG from early phenotypic observation to contemporary genomic and biomarker-driven models. It systematically evaluates the major limitations of current criteria, including the (DLCN) score, and integrates evidence from landmark Mendelian randomization (MR) studies to identify persistent gaps. A narrative synthesis of landmark clinical, epidemiological, and genetic studies was performed, encompassing the original discovery of the low-density lipoprotein cholesterol (LDL-C) receptor pathway, the development of international diagnostic criteria, and contemporary mendelian randomization (MR) evidence on the causal roles of LDL-C, lipoprotein (a) [Lp(a)], triglyceride-rich lipoprotein remnants, and apolipoprotein B (ApoB). Current diagnostic frameworks suffer from age-dependent confounding of LDL-C measurements, failure to account for Lp(a)-mediated phenocopies, inadequate discrimination between monogenic and polygenic etiologies, sex differences, ethnicity, and inapplicability to pediatric populations. MR data reveal that the causal architecture of cardiovascular risk in these disorders is particle-centric (ApoB) rather than LDL-C-centric, and that remnant cholesterol, not triglyceride per se, drives atherosclerotic cardiovascular disease risk in FHTG. We evidenced the evolution of treatment options and the morbidity and mortality rates for FH and FHTG from the 1970s until the 2020s. Future diagnostic paradigms should integrate lifetime Lp(a) measurement, polygenic risk scoring, ApoB quantification, and cascade genomic testing to replace phenotype-only approaches. This review concludes by proposing a four-step integrated diagnostic algorithm for FH and FHTG.<\/jats:p>","DOI":"10.3390\/medicina62071257","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T15:27:37Z","timestamp":1782746857000},"page":"1257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Phenotype to Genotype and Beyond: Insights into Familial Hypercholesterolemia and Familial Hypertriglyceridemia"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7378-7787","authenticated-orcid":false,"given":"Dragos","family":"Cozma","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania"},{"name":"Cardiology Department, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Research Center, Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Florin","family":"Lighezan","sequence":"additional","affiliation":[{"name":"Emergency City Hospital Timisoara, Gheorghe Dima Street Nr. 5, 300254 Timisoara, Romania"},{"name":"Centre of Advanced Research in Cardiology and Hemostasology, Faculty of the \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania"},{"name":"Department V, Internal Medicine I\u2014Discipline of Medical Semiology I, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7351-741X","authenticated-orcid":false,"given":"Cristina","family":"Tudoran","sequence":"additional","affiliation":[{"name":"Department VII, Internal Medicine II, Discipline of Cardiology, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania"},{"name":"County Emergency Hospital \u201cPius Brinzeu\u201d, L. Rebreanu, Nr. 156, 300723 Timisoara, Romania"},{"name":"Center of Molecular Research in Nephrology and Vascular Disease, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2951-8010","authenticated-orcid":false,"given":"Oana Raluca","family":"Voinescu","sequence":"additional","affiliation":[{"name":"Research Center, Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania"},{"name":"Department VI\u2014Cardiology, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6096-9601","authenticated-orcid":false,"given":"Cristian","family":"Mornos","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania"},{"name":"Cardiology Department, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Research Center, Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120650","DOI":"10.1016\/j.atherosclerosis.2026.120650","article-title":"Risk Factors for Atherosclerotic Cardiovascular Disease in Individuals with Heterozygous Familial Hypercholesterolemia: A Systematic Review and Meta-Analysis","volume":"415","author":"Pang","year":"2026","journal-title":"Atherosclerosis"},{"key":"ref_2","unstructured":"Daley, S.F., Cusick, A.S., and Reilly, E. 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