Key result
Targeted NGS and 12-SNP genotyping in clinically diagnosed FH patients identified pathogenic variants in 34%, while high LDL polygenic risk scores were found in 64% of variant-negative patients.
Observational (n=116)
Both monogenic pathogenic variants and polygenic factors contribute to familial hypercholesterolemia in South Indian patients, with high LDL-PRS further increasing CAD risk in variant-positive individuals.
Heterozygous familial hypercholesterolemia (FH), a monogenic cause for premature coronary artery disease (CAD) is often underdiagnosed. In individuals who meet the FH diagnostic criteria and lack pathogenic variants, polygenic factors are recognized as potential contributors. This study aimed to characterize the spectrum of genetic variants and determine the low-density lipoprotein polygenic risk score (LDL-PRS) among clinically diagnosed FH participants from South India. We recruited 116 unrelated participants with a pretreatment LDL- C concentration ≥ 190 mg/dl and a DLCN (Dutch Lipid Clinic Network) score ≥ 3. Targeted next-generation sequencing (NGS) of 23 lipid related genes and 12-SNP (Single nucleotide polymorphism) genotyping were performed. NGS identified 39 variants including 13 pathogenic and 26 variants of unknown significance (VUS) some of which were in non-classical genes: ABCG5, ABCG8, APOE, PPP1R17, SREBF2. Pathogenic variants were detected in 66.7% of those with definite FH,19.7% in probable FH and 2.7% in possible FH. Overall,66% were variant negative. Among variant negative (FH/V-) participants, 64% demonstrated high LDL-PRS, whereas 70% of variant positive participants also exhibited elevated scores; suggesting a contributory role of polygenic factors across both groups. Additionally, the observation that variant positive individuals with high LDL-PRS have an increased risk of coronary artery disease (CAD) adds important nuance to risk stratification within genetically confirmed FH patients. Confirmation of diagnosis by genetic testing is essential for the diagnosis of FH. Although LDL-PRS may offer little benefit in variant negative cases and improve CAD risk prediction in variant positive individuals, large scale studies are essential to validate its clinical utility and assess whether inclusion of additional LDL- raising SNPs could enhance the detection of polygenic FH in the Indian population.
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Abraham et al. (2026) conducted an observational in Familial hypercholesterolemia (n=116). Targeted next-generation sequencing and 12-SNP LDL polygenic risk score was evaluated on Detection of pathogenic variants and high LDL-PRS. Targeted NGS and 12-SNP genotyping in clinically diagnosed FH patients identified pathogenic variants in 34%, while high LDL polygenic risk scores were found in 64% of variant-negative patients.
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