Purpose of review: This review examines the role of copy number variation in the human genome as a newly recognized determinant of lipoprotein and metabolic phenotypes.
Recent findings: Much of the recent progress defining the molecular basis of lipoprotein disorders has been the result of studying genomic DNA at the single nucleotide level, for instance with nucleotide sequence analysis or genotyping to detect single nucleotide polymorphisms. Focus on single nucleotides, however, fails to capture the complete spectrum of potential genetic variability. Recent genome-wide mapping studies have demonstrated the surprising ubiquity of large-scale copy number variations in apparently healthy people, adding to the complexity of the 'normal' genome, but also emphasizing this form of genetic variation as a potential disease mechanism. The application of this understanding to the genetics of lipoprotein disorders has been rapid. For instance, the use of novel techniques to detect copy number variations, such as multiplex ligation-dependent probe amplification, has revealed many additional causative mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia.
Summary: Copy number variations thus represent a new level of genomic variation that is both an important mechanism of monogenic lipoprotein disorders and a potential contributor to common complex lipoprotein and metabolic phenotypes in the general population.