Genetics
Splice-site CETP mutations are found in 10% of a South Indian familial hypercholesterolemia cohort (Cureus 2025)
Original title: The Genetic Landscape of Familial Hypercholesterolemia in Telangana, Southern India: Novel Mutations and Clinical Implications
Researchers used the Dutch Lipid Clinic Network score to identify suspected familial hypercholesterolemia probands in Telangana State, India, followed by cascade screening of first-degree relatives, targeted exome sequencing and pedigree analysis in 30 individuals. They identified novel and known high-impact mutations across several FH-related genes, including stop-gain mutations in LPL (6 of 30, 20%) and LDLR (4 of 30, 13.3%), and splice donor site mutations in SLCO1B1 (1 of 30, 3.3%) and CETP (3 of 30, 10%). A novel LDLR frameshift mutation was found in two siblings, one homozygous and meeting Definite FH classification, while variants in APOA5 and LDLR correlated with higher DLCN scores and variants in ABCG5 and ABCG8 correlated with lower LDL cholesterol, highlighting the genetic heterogeneity of FH in this Indian population.
Original abstract
Background: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, leading to premature cardiovascular disease (CVD). This study aimed to identify genetic variants associated with FH in patients from Telangana State, India.
Methods: Probands with suspected FH were identified using the Dutch Lipid Clinic Network (DLCN) score, followed by cascade screening of their first-degree relatives. Targeted exome sequencing and pedigree analysis were performed to identify FH-associated genetic variants.
Results: We identified both novel and known high-impact mutations in genes implicated in FH pathogenesis, including stop-gain mutations in LPL (6/30; 20%) and LDLR (4/30; 13.3%), as well as splice donor site mutations in SLCO1B1 (1/30; 3.3%) and CETP (3/30; 10%). Notably, a novel frameshift mutation in LDLR was identified in two siblings (2/30; 6.7%), one of whom (50%) exhibited a homozygous variant and met the "Definite FH" classification based on the DLCN criteria. Additionally, moderate-impact variants rs2075291 (APOA5) and rs193922571 (LDLR) showed strong correlations with the DLCN score, suggesting increased susceptibility to FH. In contrast, rs6756629 (ABCG5) and rs11887534 (ABCG8) were strongly negatively correlated with LDL-C levels and the DLCN score, indicating potential protective effects against FH.
Conclusions: These findings highlight the genetic heterogeneity of FH and emphasize the importance of identifying novel pathogenic variants. Moreover, the study underscores the role of moderate-impact variants in FH susceptibility. Overall, this research enhances our understanding of the genetic landscape of FH in the Indian population, with implications for improved diagnosis, risk assessment, and personalized management.
familial hypercholesterolaemiagenetics
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.