Exome sequencing: new insights into lipoprotein disorders

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Medicine

Background:

• Monogenic dyslipidemias are severe inherited lipid disorders.
• Next-generation sequencing (NGS) platforms enable DNA-to-diagnosis protocols.
• Previous studies often identified variants in known lipid genes.

Purpose of the Study:

• To evaluate the effectiveness of whole genome/exome sequencing versus targeted sequencing for diagnosing monogenic dyslipidemias.
• To determine if novel genes for lipid regulation can be identified through high-throughput sequencing in unexplained cases.

Main Methods:

• Review of recent reports on whole genome and whole exome sequencing applications in families with severe dyslipidemias.
• Analysis of high-throughput DNA sequencing data from families with uncharacterized monogenic dyslipidemias.

Main Results:

• Whole genome or whole exome sequencing primarily identified variants in established lipid genes.
• High-throughput sequencing failed to uncover new genes involved in plasma lipid regulation in previously uncharacterized families.

Conclusions:

• A targeted sequencing approach focusing on known lipoprotein metabolic pathway genes is recommended for diagnosing most monogenic dyslipidemias.
• Whole genome or whole exome sequencing may not be the most efficient strategy for identifying the molecular basis of these conditions.