Molecular screening of familial hypercholesterolemia in Icelanders

Abstract

Familial hypercholesterolemia (FH) is a monogenic disease characterized by a lifelong exposure to high LDL-C levels that can lead to early onset coronary heart disease (CHD). The main causes of FH identified to date include loss-of-function mutations in LDLR or APOB, or gain-of-function mutations in PCSK9. Early diagnosis and genetic testing of FH suspects is critical for improved prognosis of affected individuals as lipid lowering treatments are effective in preventing CHD related morbidity and mortality. In the present study, we carried out a comprehensive screening, using a next-generation sequencing (NGS) panel, for FH culprit mutations in two Icelandic studies representative of either FH families or the general population. We confirmed all previously known mutations in the FH families, and identified two subjects that had been misdiagnosed clinically at young age. We identified six new mutations in the Icelandic FH families and detected three pathogenic mutations in the general population-based study. The application of the NGS panel revealed substantial diagnostic yields in identifying pathogenic mutations, or 68.2% of those with definite clinical diagnosis of FH in the family material and 5.6-fold enrichment in the population-based genetic testing.

Keywords:

• Cholesterol
• dyslipidemias
• high-throughput nucleotide sequencing
• genetic testing
• LDLR mutations

Acknowledgments

We thank the study subjects and family members who consented to participate in this research project. We thank Ed O’Neill for editorial comments on the manuscript.

Author contributions

All authors contributed to the study, approved the final draft and agree with the analyses of the data and the conclusions reached in the manuscript. VE, GK, OP and BT conceived of the study, analyzed the data, wrote, and edited the manuscript.

Disclosure statement

VE, VG and BT declared they do not have anything to disclose about conflict of interest with respect to this manuscript. All other authors are employees at the company Phosphorus.