👤 Ariyanachi K

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. 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. 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. 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. Show less

Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population-based allele frequencies. From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy. Show less