Familial hypercholesterolemia (FH) is a common genetic disorder characterized by elevated LDL cholesterol and increased risk of premature cardiovascular disease. The genetic landscape of FH in the Indonesian population remains largely uncharacterized.

We analyzed 486 Indonesian participants with whole genome sequencing (WGS) and LDL data from the Genesis-ID cohort at Biobank RSUPN Dr. Cipto Mangunkusumo. WGS was performed by BB Binomika, Ministry of Health Indonesia, using Illumina Novaseq 6000 with average coverage ≥30X. Primary and secondary analyses up to variant calling (VCF) were conducted by BB Binomika, while tertiary analyses including variant annotation, filtering, and interpretation were performed by the Clinical Research Unit at RSUPN Dr. Cipto Mangunkusumo. Variant annotation was performed using VEP (ENSEMBL v114.2) with additional ClinVar database annotations (2025-02-27), followed by manual curation using gnomAD v4 and SpliceAI predictions. Variants were filtered based on relevance to FH genes (LDLR, PCSK9, APOB, LDLRAP1) and interpreted according to ACMG (2015) and ClinGen FH Expert Panel specifications v1.2.

Among the participants, FH variants were classified as benign (n=433, 89.1%), likely benign (n=7, 1.4%), variants of uncertain significance (VUS n=55, 11.3%), likely pathogenic (n=1, 0.2%), and pathogenic (n=4, 0.8%). Pathogenic variants were identified in LDLR and a likely pathogenic variant in APOB. LDLR pathogenic variants included c.13028_13029del (p.Tyr4343CysfsTer3), c.718C>T (p.Gln240Ter), c.1120G>A (p.Glu374Lys), and c.918del (p.Asp307ThrfsTer44), while the APOB likely pathogenic variant was c.718C>T (p.Gln240Ter). Median LDL levels, adjusted for lipid-lowering therapy, ranged between 129–229 mg/dL depending on FH category. DLCN scores incorporating clinical history reflected elevated risk for individuals with pathogenic or likely pathogenic variants.

This study provides the first comprehensive overview of FH genetic profiles in an Indonesian cohort. Integrating genetic testing with clinical evaluation, LDL-adjusted measurements, and DLCN scoring allows for accurate diagnosis, risk stratification, and personalized management of FH in Indonesia. Early identification of pathogenic variants in LDLR and APOB supports targeted intervention and highlights the need for national strategies to implement genetic screening and precision management for FH patients.