Diagnostic Yield and Clinical Phenotype in a Lithuanian Familial Hypercholesterolemia Cohort with Heterogeneous Sequencing Platforms

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• Picked for Genetics (clinical) (top studies of the week, 1 November 2026): FH diagnostic yield and sequencing limitations inform genetic testing practice

Abstract

Background and Objectives: This study aimed to determine the diagnostic yield of familial hypercholesterolemia (FH) genotyping and to describe the clinical phenotype and pharmacogenomic (PGx) implementation readiness of adults referred for clinically suspected FH at a Lithuanian tertiary cardiology center. The study was designed as a descriptive retrospective analysis of existing clinical and genetic test results generated using heterogeneous historical sequencing platforms. Materials and Methods: This single-center descriptive cohort included 48 adults with clinically suspected FH evaluated between February 2022 and June 2023. Patients were classified according to Dutch Lipid Clinic Network criteria before genetic testing. Historical targeted next-generation sequencing (NGS) and whole-exome sequencing (WES) results were reviewed. Genetic findings were interpreted using a three-tier reporting framework: diagnostic FH-associated findings, pharmacogenomic findings relevant to future implementation, and VUS, common polymorphisms, or other non-diagnostic findings. Because harmonized PGx star-allele/diplotype calling was not available across historical platforms, PGx findings were not analysed as a mutually exclusive patient-level category. Results: Pathogenic FH-associated variants were identified in 13 of 48 patients (27.1%), including eight LDLR and five APOB variant carriers. In the remaining 35 patients (72.9%), no pathogenic or likely pathogenic FH-associated variant was identified within the analytical scope of the historical test used. This non-diagnostic category could include VUS, common polymorphisms, exploratory findings, or no reportable variant. Patients carrying pathogenic LDLR variants had higher total cholesterol and LDL-C concentrations than patients without detected pathogenic variants. PGx-related findings were considered observations relevant to reporting and future implementation; they were not evaluated as predictors of statin response, statin intolerance, or LDL-C reduction. Conclusions: In this Lithuanian real-world cohort, pathogenic LDLR or APOB variants were identified in 27.1% of patients referred for suspected FH. Retrospective analyses of heterogeneous historical genetic results can inform diagnostic reporting and implementation planning but cannot establish PGx associations with statin efficacy or intolerance without harmonized diplotype calling and prospectively collected treatment outcomes.

Abstract as published, via PubMed.