Clinical whole exome sequencing in severe hypertriglyceridemia

Area of Science:

• Genetics
• Molecular Biology
• Clinical Diagnostics

Background:

• Severe hypertriglyceridemia (HTG) lacks extensive data on molecular diagnostics.
• Understanding the genetic basis of severe HTG is crucial for effective treatment.

Purpose of the Study:

• To evaluate the clinical utility of whole exome sequencing (WES) for diagnosing severe HTG.
• To identify causative genetic variants and potential novel mechanisms in severe HTG.

Main Methods:

• Whole exome sequencing (WES) was performed on 28 probands with severe HTG (≥1000 mg/dl).
• Analysis included recessive and dominant inheritance models, gene prioritization, and copy number variation (CNV) analysis.

Main Results:

• Causative variants were identified in 32% (9/28) of probands, including three novel variants.
• Recessive variants in LPL and compound heterozygous variants in LPL/APOA5 were found.
• Dominant variants in LPL, GCKR, and SLC25A40 were associated with the HTG phenotype.

Conclusions:

• Whole exome sequencing (WES) identified potential causative variants in nine genes linked to rare Mendelian dyslipidemias.
• Clinical WES is a feasible diagnostic tool for severe HTG cases.
• Molecular diagnosis can facilitate targeted therapeutic strategies.