Editors' ChoiceHuman Genomics

Exomes Take Center Stage

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Science Translational Medicine  03 Nov 2010:
Vol. 2, Issue 56, pp. 56ec171
DOI: 10.1126/scitranslmed.3001854

The human exome (comprising all protein-coding sequences of the genome) represents just 1% of the 6 billion nucleotides in the diploid human genome. Yet, surprisingly, more than 80% of genetic diseases showing Mendelian inheritance stem from mutations in the exome. Accordingly, genome-wide sequencing of the human exome represents a potentially powerful way to detect new disease-causing mutations.

In their new study, Musunuru et al. provide evidence of the power of this strategy by studying a family suffering from a rare inherited disorder of lipid metabolism known as familial combined hypolipidemia (FCH). Individuals with this disorder have characteristically low cholesterol levels and show a lifelong protection against coronary artery disease. Interestingly, although some FCH patients harbor mutations in the gene encoding apolipoprotein B, the genetic mutations underlying the disease in others is not known. In an effort to identify the causative genetic mutations in other FCH patients, the investigators sequenced the entire exomes of two siblings with FCH and compared these sequences to the exomes of 60 other individuals. More than 16,000 genes were targeted for sequencing, with over 6 billion bases of sequence generated for each FCH patient. By assuming a recessive model of inheritance and eliminating any variants found in the 60 control exomes or documented in existing databases, the investigators hit gold. They identified two rare homozygous nonsense mutations in the gene encoding the angiopoietin-like 3 protein (ANGPTL3). They then expanded their investigation to 36 other members of this family and discovered that the two nonsense alleles segregated independently. There was a significant gene dose effect regarding the ANGPTL3 variants found in other family members. Those that were heterozygous for the mutations had substantially lower LDL cholesterol (72 mg/dl versus 109 mg/dl) and triglyceride (64 mg/dl versus 130 mg/dl) levels compared with family members who did not carry either of the ANGPTL3 mutations.

ANGPTL3 is primarily expressed and secreted in the liver, and inactivation of the gene encoding this protein leads to lower plasma cholesterol in mice. Notably, the functional mechanism behind this effect is not yet fully understood. Nevertheless, we can be sure that ANGPTL3 will be an important future target for developing new cholesterol-lowering drugs. There is no doubt that complete exome sequencing in search of disease-causing mutations has taken center stage.

K. Musunuru et al., Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 13 October 2010 (10.1056/NEJMoa1002926). [Abstract]

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