Abstract 12685: Searching for Novel Variants in Familial Hypercholesterolemia by Exome Sequencing
Familial hypercholesterolemia (FH) is an autosomal dominant disease, characterized by very high serum cholesterol and development of premature coronary artery disease. Most pathogenic mutations of FH are in low-density lipoprotein-receptor (LDLR) genes, however, in a large part of possible FH patients, known single gene mutations cannot be found. The aim of this study was to check mutation prevalence in Korean FH patients and to identify variants in mutation-negative FH using exome sequencing.
Forty-eight unrelated FH patients and were enrolled after diagnosis by Simon Broome criteria from 9 sites in Korea. Average age was 53 years, females were 56%. To identify causal variants for each FH patient, we performed whole exome sequencing in 48 FH patients. The bases covered at least 8x mean coverage depth was 90%. In screening known causing mutations registered in public databases, 14 of 48 sequenced patients had pre-identified mutations in LDLR gene. In addition, we identified known causal variants in APOB and PCSK9 gene in one and another patient, respectively. In the second step, 3 novel mutations in LDLR gene and one novel mutation in apoB gene were identified. Three novel LDLR mutations were proven to be pathogenic by screening family members, while a apoB mutation was not. Further, we applied multiple statistical algorithms (joint rank sum approach) to rank highly relevant genes for the disease, segregating thousands of rare variants compared to 276 whole exome sequencing data of healthy Korean controls and 287 East Asians in 1000 genome project. We prioritized some candidate disease-causing genes (Figure and Table). In this presentation, we will discuss the utility of exome sequencing as a diagnostic tool for FH.
- © 2013 by American Heart Association, Inc.