Familial hypercholesterolemia - Targeted whole gene sequencing as a diagnostic approach

Area of Science:

• Genetics
• Molecular Biology
• Pharmacogenomics

Background:

• Familial hypercholesterolemia (FH) is a common, underdiagnosed genetic disorder.
• Current screening methods are limited by cost.
• Accurate molecular diagnosis is crucial for effective treatment.

Purpose of the Study:

• To design and implement a whole gene targeted next-generation sequencing (NGS) panel.
• To achieve high-quality variant calling, including copy number analysis.
• To facilitate molecular diagnosis of FH and statin intolerance.

Main Methods:

• Developed a hybridisation-based, short-read NGS panel covering dominant (LDLR, APOB, PCSK9, APOE) and recessive (LDLRAP1, ABCG5/8, LIPA) FH genes.
• Included SLCO1B1 for statin intolerance and polygenic risk score markers.
• Applied the panel to a Swedish FH study population (n=133).

Main Results:

• Achieved high coverage and confident variant calling across all targeted genes.
• Identified known causal variants in 43% of the cohort within dominant FH genes.
• Detected copy number variants in LDLR and a whole gene deletion in SLCO1B1, alongside various coding and non-coding variants.

Conclusions:

• The developed NGS panel provides a comprehensive, high-quality tool for molecular genetic analysis of FH.
• It aligns with current guidelines for FH diagnosis and treatment.
• The findings highlight the need for extended gene panels to capture diverse genetic variations.