Important Aspects

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

Riccio et al. (1) found that in the general population of Germany, 97.7% of persons with an LCL-C measurement ≥190 mg/dL have no pathogenic variant for familial hypercholesteremia (FH), which they claim indicates a low diagnostic yield of population based genetic screening. Some important aspects of this work need to be considered.

• The authors did not identify any carriers of the APOB R3527Q variant, although 6–7 were to be expected, which raises doubt in their genetic tests.
• Only half of the observed variants in the canonical FH genes have thus far been completely annotated (7); many variants that are present in their cohort may have been erroneously annotated as not pathogenic.
• With increasing age, the LDL-C difference between FH and the general population declines. An age range of 45–60 years is therefore suitable to a limited degree only for confirming the use of LDL-C measurement for the diagnosis of FH. Before genetic tests, the pretest probability should be assessed, which is based on the presence of early atherosclerosis, a familial history of hypercholesteremia, xanthoma, or xanthelasma (3). The Dutch Lipid Clinical Network (DLCN) score is appropriate for the clinical assessment.
• A high concentration of lipoprotein (a) can be responsible for the FH phenotype in some 14% of patients with suspected FH (4).
• Before initiating a genetic test, the usual practice is to rule out known causes of secondarily raised LDL-C (hypothyroidism, cholestasis, nephrotic syndrome, and medication intake).
• Polygenic hypercholesteremia was not considered (4).

We suspect that the analysis of the authors’ data would yield different results if these aspects were considered.

DOI: 10.3238/arztebl.m2026.0012

Prof. i. R. Dr. med. Winfried März

SYNLAB Holding Deutschland GmbH, SYNLAB Akademie, Mannheim

Klinik für Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg

DACH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., Hamburg

Em. Prof. Dr. Steve E. Humphries

Institute of Cardiovascular Science, University College London, London, United Kingdom

Conflict of interest statement

WM received financial funding, consultancy and lecture honoraria, and reimbursement of travel expenses from AMGEN, Sanofi, Amryt Pharmaceuticals, Abbott Diagnostics, Akzea Therapeutics, Novartis Pharma, SOBI, Ultragenyx, and Berlin-Chemie. He is an advisory board member in the listed companies and sits on the board of the DACH Society for the Prevention of Heart and Circulatory Diseases reg. assoc.

SH declares that no conflict of interest exists.

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. Tabet DR, Cote AG, Lancaster MC, et al.: The functional landscape of coding variation in the familial hypercholesterolemia gene LDLR. Science 2025: eady7186

3. Klose G, Laufs U, Marz W, Windler E: Familial hypercholesterolemia: Developments in diagnosis and treatment. Dtsch Arztebl Int 2014; 111: 523–9

4. Humphries SE, Futema M: Genetic determinants of the familial hypercholesterolaemia phenotype. Ann Hum Genet 2025; 89: 293–304