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Published on: September 15, 2018
Molecular screening of familial hypercholesterolemia in Icelanders
Greg Kellogg1, Bolli Thorsson2, Ying Cai1
1Phosphorus Diagnostics, New York, NY, USA.
Insights
Next-generation sequencing effectively identifies mutations causing familial hypercholesterolemia (FH). This genetic testing improves diagnosis for FH families and the general population, aiding early intervention for coronary heart disease prevention.
Area of Science:
- Genetics
- Cardiovascular Disease
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL-C levels and early coronary heart disease (CHD).
- Key genetic causes include mutations in LDLR, APOB, or PCSK9.
- Early diagnosis and genetic testing are crucial for effective CHD prevention through lipid-lowering treatments.
Purpose of the Study:
- To conduct comprehensive screening for FH-causing mutations using a next-generation sequencing (NGS) panel.
- To evaluate the diagnostic yield of NGS in Icelandic FH families and a general population cohort.
Main Methods:
- Utilized a next-generation sequencing (NGS) panel for mutation screening.
- Analyzed samples from Icelandic FH families and a general population study.
Main Results:
- Confirmed known mutations in FH families and identified six new pathogenic mutations.
- Detected three pathogenic mutations in the general population cohort, revealing a 5.6-fold enrichment.
- Achieved a 68.2% diagnostic yield in individuals with a definite clinical FH diagnosis within families.
- Identified two cases of misdiagnosis in young individuals.
Conclusions:
- NGS panels offer substantial diagnostic utility for identifying FH-related mutations.
- Genetic testing via NGS enhances FH diagnosis in both familial and general population settings.
- Improved diagnostic accuracy facilitates timely treatment and CHD risk reduction.
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.
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