In Reply

Letters to the Editor regarding the article Familial Hypercholesterolemia: Prevalence and Discrepancy Between Genotype and Phenotype Findings of the Population-Based Hamburg City Health Study by Cristian Riccio, Natalie Arnold, Georgios Koliopanos, Vivian Link, Linlin Guo, Raphael O. Betschart, Tanja Zeller, Stefan Blankenberg, Andreas Ziegler, and Raphael Twerenbold in issue 19/2025

The focus of our population-based analysis was to determine the prevalence of genetically confirmed familial hypercholesterolemia (FH) in the general adult population of Hamburg and to examine its relation to the phenotype. The estimated prevalence of 1:321 (1) is consistent with population-based data from other settings worldwide (2) and, in principle, may also be generalizable to younger populations.

The key finding of our study—the discrepancy between genotype and phenotype—is not a methodological artefact. Rather, it is in line with the current epidemiological evidence on FH given the FH-associated variants annotated to date (3). This discrepancy further underscores that the genetic basis of severe hypercholesterolemia is heterogeneous and complex, extending well beyond classic monogenic FH. Additional causes should also be systematically considered, including as yet unannotated FH variants, structural variants, secondary forms of hypercholesterolemia, and FH-like phenotypes such as those associated with elevated lipoprotein(a) (Lp(a)) levels (4). We will address those questions in future analyses. We agree that the relative contribution of these causes changes with age. In childhood, for example, classic FH forms account for a relatively larger proportion of severe hypercholesterolemia than in adulthood (1).

From our perspective, it is essential to distinguish between two concepts: epidemiological-genetic screening in the general population is not equivalent to a systematic lipid clinic work-up. Genetic testing should, of course, be used in individuals with a high pre-test probability based on clinical criteria. Moreover, the immediate therapeutic implications of genetically confirmed FH in individuals with only moderate LDL-C levels or an entirely unremarkable lipid profile remain incompletely understood. Against this background, we would also like to address the point raised regarding genetic diagnostics: variant annotation in FH genes remains incomplete and, in some instances, inconsistent; for many variants, functional data are still lacking (5). For example, in ClinVar, the variant APOB R3527Q is—in addition to FH—also associated with hypobetalipoproteinemia, which led us to omit this variant from our analysis (1).

For cardiovascular prevention and clinical care, one point remains central: we do not question the value of early phenotype-based screening. LDL-C remains the key actionable parameter. The increased cardiovascular risk in genetically confirmed FH (3) reflects the lifelong cumulative exposure to LDL-C. If clinically relevant hypercholesterolemia is identified early on a phenotypic basis and treated consistently, the cardiovascular risk can be notably reduced. A pragmatic approach would therefore be early and broad LDL-C assessment, ideally together with Lp(a). This could be implemented, for example, within pediatric preventive care or dedicated programs for adolescents and young adults. Cascade screening can also be easily performed on a phenotypic basis, even without molecular genetic testing.

In conclusion, the discussion should not frame genetics and phenotype as opposing concepts, but rather emphasize one shared goal: the development of valid, pragmatic, and evidence-based screening strategies for FH across all age groups.

DOI: 10.3238/arztebl.m2026.0013

On behalf of the authors

Dr. med. Natalie Arnold

Universitäres Herz- und Gefäßzentrum Hamburg, Klinik für Kardiologie,

Universitätsklinikum Hamburg-Eppendorf, Hamburg

Cristian Riccio, Ph.D.

Cardio-CARE, Medizincampus Davos, Davos, Schweiz

Prof. Dr. med. Stefan Blankenberg

Universitäres Herz- und Gefäßzentrum Hamburg, Klinik für Kardiologie,

Universitätsklinikum Hamburg-Eppendorf, Hamburg

Prof. Dr. rer. nat. Andreas Ziegler

Cardio-CARE, Medizincampus Davos, Davos, Schweiz

Prof. Dr. med. Raphael Twerenbold

Universitäres Herz- und Gefäßzentrum Hamburg, Klinik für Kardiologie,

Universitätsklinikum Hamburg-Eppendorf, Hamburg

Conflict of interest statement

NA received consultancy fees from Novartis. She received lecture fees from Amgen, Novartis, Daiichi Sankyo, and Sanofi; research funding from Novartis, and reimbursement of travel expenses from Daiichi Sankyo. NA also received consulting fees (advisory boards) from Arrowhead and Apontis Pharma.

SB received lecture fees from Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, and GSK plc. SB is a member of advisory boards and consultant for Thermo Fisher Scientific. He is honorary president of the German Cardiac Society and honorary spokesperson of the German Center for Cardiovascular Research, partner site North. He is also honorary board member of the Global Cardiovascular Research Funder Forum. He is scientific consultant of Cardio-CARE, a 100% nonprofit subsidiary of the Kühne Foundation.

AZ is an honorary board member of the Basel Biometric Society. He is scientific director and managing director of Cardio-CARE, a 100% nonprofit subsidiary of the Kühne Foundation.

AZ, RT, and SB are listed as co-developers of an international patent for the use of a computer-implemented system for assessing the likelihood of myocardial infarction (international publication number WO2022043229A1, TW202219980A). AZ, RT, and SB are co-founders of ART-EMIS. AZ and SB sold their shares in 2023.

CR is a bioinformatician at Cardio-CARE. Cardio-CARE is a shareholder of ART-EMIS Hamburg.

RT received study support from Kühne Foundation and lecture fees from Amgen.

References

1. Riccio C, Arnold N, Koliopanos G, et al.: Familial hypercholesterolemia: Prevalence and discrepancy between genotype and phenotype. Findings of the population-based Hamburg City Health Study. Dtsch Arztebl Int 2025; 122: 511–6

2. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG: Worldwide prevalence of familial hypercholesterolemia: Meta-analyses of 11 million subjects. J Am Coll Cardiol 2020; 75: 2553–66

3. Khera AV, Won HH, Peloso GM, et al.: Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol 7; 67: 2578–89

4. Hedegaard BS, Nordestgaard BG, Kanstrup HL, et al.: High lipoprotein(a) may explain one-quarter of clinical familial hypercholesterolemia diagnoses in Danish lipid clinics. J Clin Endocrinol Metab 2024; 109: 659–67

5. Chora JR, Medeiros AM, Alves AC, Bourbon M: Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: Application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet Med 2018; 20: 591–8