F amilial hypercholesterolemia (FH) is a relatively common disorder, previously thought to have a monogenic basis. 1 The paradigmatic heterozygous form of FH (HeFH) is characterized by lifelong elevations in plasma low-density lipoprotein (LDL) cholesterol, typically >5.0 mmol/L (194 mg/dL), sometimes occurring with characteristic physical signs and frequently with a personal or family history of early cardiovascular disease (CVD).1 Recent populationbased surveys, including screening with DNA sequencing, suggest that HeFH has a prevalence of ≈1 in 217 individuals in Northern Europe.2 Large-scale whole-exome sequencing efforts indicate that ≈4% of individuals with early coronary heart disease have HeFH resulting from one of several lossof-function mutations in the LDLR gene encoding the LDL receptor.3 Other large-scale sequencing efforts indicate that within subgroups of individuals with severe hypercholesterolemia, defined as untreated LDL cholesterol >5.0 mmol/L (>194 mg/dL), only ≈2% had a pathogenic mutation in an autosomal dominant FH gene. Objective-Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic. Approach and Results-We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia-causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL). Conclusions-In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores.
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