Genetic analysis of familial hypercholesterolemia in Asian Indians: a single center study

Abstract Background Familial Hypercholesterolemia (FH), an autosomal co-dominant disorder characterized by very high LDL cholesterol, is strongly associated with premature coronary artery disease. Objectives Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives and cascade screening in their relatives. Methods Potential cases of FH (n=100), were identified by criteria adapted for the Indian population from Dutch Lipid Clinic Network (DLCN) criteria. Pathogenic variants were analyzed in LDLR, APOB 100 (exons 26 and 29), PCK9 and APOE genes using Sanger sequencing, and MLPA technique. Cases in whom there were no pathogenic variants were tested by Next Generation Sequencing (NGS) using a targeted panel of genes. Results Thirty-eight pathogenic variants were identified in 47 of 100 unrelated probands. Of these variants, 33 were in LDLR, 3 in APOB and 2 in PCSK9 genes. Ten pathogenic variants were novel. Mutations were detected in 91.4% of those subjects classified as Definite, 40% as Probable and in 18.8% as Possible FH cases based on modified DLCN criteria. A likely founder mutation in intron 10 (c.1587-1G>A) of LDLR gene was observed in 6 North Indian families. The conventional pathogenic variants in APOB and PCSK9 genes, and those previously reported in LDLR gene among Asian Indians were not detected in this cohort. Conclusion This study demonstrates genetic heterogeneity of FH in India. The variants observed were different from those described in Western populations. NGS technology helped to identify new mutations in APOB gene, suggesting that in less studied populations it is better to sequence the whole gene rather than test for specific mutations.