Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia

Abstract

We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).

Figure 1. Pedigree of the Study Family with Familial Combined Hypolipidemia

Squares indicate male family members, and circles female family members. Slashes indicate deceased persons. Roman numerals to the left of the pedigree indicate the generation; numerals to the upper left of each symbol indicate the individual family member. For the ANGPTL3 genotype, the X denotes a stop codon. The column of five values under each symbol indicates, from top to bottom, the age in years (as of 1997) and the total cholesterol, triglyceride, and LDL and HDL cholesterol levels (all in milligrams per deciliter). The values are the means of measurements from multiple fasting lipid profiles. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129.

Figure 2. Phenotypes Associated with Familial Combined Hypolipidemia in the Study Family, According to Number of Mutant ANGPTL3 Alleles

Shown are the levels of low-density lipoprotein (LDL) cholesterol (Panel A), triglycerides (Panel B), and high-density lipoprotein (HDL) cholesterol (Panel C) in the family members, grouped according to ANGPTL3 genotype. The corresponding “residual” phenotypes are shown (in Panels D, E, and F, respectively), in units normalized to the standard deviation, after adjustment for age, age squared, and sex. The box plots give the median levels (middle horizontal line in each box), the interquartile ranges (delineated by the top and bottom of each box), and outliers falling below the 5th percentile or above the 95th percentile (points below or above the vertical lines, respectively). To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129.