PLoS One. 2026 Jul 9;21(7):e0353401. doi: 10.1371/journal.pone.0353401. eCollection 2026.
ABSTRACT
BACKGROUND: Familial hypercholesterolaemia (FH) is an inherited disorder with markedly elevated LDL-C and increased risk of premature atherosclerotic cardiovascular disease, most often caused by pathogenic variants in LDLR and less frequently APOB/PCSK9 (or recessive LDLRAP1). FH is commonly assessed using the Dutch Lipid Clinic Network (DLCN) score (definite >8, probable 6-8, possible 3-5). In Uzbekistan, genetic evidence for FH remains limited and largely based on candidate-variant studies, and the diagnostic yield of NGS for monogenic FH in CAD patients is not well defined.
AIM: For the first time in Uzbekistan and Central Asia, to investigate FH-associated monogenic variants using next-generation sequencing (NGS) and to assess the validity of the DLCN criteria against genetic testing as the diagnostic reference standard in Uzbek patients with CAD and suspected FH.
METHODS: This study included 95 patients with coronary artery disease (CAD) who underwent targeted NGS of LDLR, APOB, PCSK9, and LDLRAP1. The suspected/phenotypic FH group comprised 56 patients: 53 with DLCN-predicted heterozygous FH (HeFH)-possible (3-5 points, n = 22), probable (6-8 points, n = 16), and definite (>8 points, n = 15)-and 3 siblings from one family with a homozygous FH (HoFH) phenotype. The control group included 39 CAD patients with hypercholesterolemia without an FH diagnosis (DLCN 1-2 points). Only pathogenic/likely pathogenic (P/LP) variants were used for genetic confirmation of FH.
RESULTS: Pathogenic/likely pathogenic variants were detected in 10/53 (18.9%) DLCN-predicted HeFH patients and in all three HoFH siblings. Genetic confirmation rates (PPV) were 46.7% (7/15) in definite HeFH, 12.5% (2/16) in probable HeFH, and 4.5% (1/22) in possible HeFH; no P/LP variants were detected in controls (0/39). Using a DLCN >8 threshold, sensitivity was 70.0% (7/10) and specificity was 90.2% (74/82) in the CAD cohort excluding the HoFH family.
CONCLUSION: NGS confirmed the highest diagnostic yield in patients with DLCN >8, supporting its use as a practical threshold to prioritise genetic testing; however, monogenic FH may still be present in patients with probable or possible DLCN scores.
PMID:42424361 | DOI:10.1371/journal.pone.0353401