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Improved FH Diagnosis Using Expanding Genetic Analysis
Quick Takes
- It is necessary to have a high index of suspicion for familial hypercholesterolemia (FH). The majority of FH is polygenic, but when heterozygous FH is documented, there is a four-fold increased risk for CAD at the same LDL-C level.
- Genetic testing is needed to help decide intensity of treatment and obtain approval for PCSK9 antibody drugs in persons without atherosclerotic cardiovascular disease and provide family counseling.
- Expanding testing to small-scale variants and large-scale copy number variants is available clinically in some commercial vendors without additional charge.
Study Questions:
What is the value of expanding the genetic testing to include the variant spectrum of heterozygous familial hypercholesterolemia (HeFH) in clinical practice?
Methods:
A total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable HeFH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of nine genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8) including the evaluations of small-scale variants and large-scale copy number variants (CNVs).
Results:
Among the 169 clinical HeFH patients, 98 (58.0%) were men, average age was 45 ± 14 years, xanthoma/corneal arcus was present in 17.5%, 71% had coronary artery disease (CAD), 38.7% had definite clinical HeFH and remaining probable; 70% were on statins with mean low-density lipoprotein cholesterol (LDL-C) 224 ± 93 mg/dl and apolipoprotein B 151 ± 51 mg/dl. A total of 85 (68.5%) index cases carried HeFH-associated variants. The proportion of HeFH caused by small-scale variants in LDLR, APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were included. Furthermore, the variants in LDLR, APOB, and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were eight non-LDLR CNVs detected in the present study; 10% of index cases were compound heterozygotes and 3.2% were homozygous FH.
Conclusions:
LDLR, APOB, and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic HeFH, suggesting that an expanding genetic testing may be considered to further detect HeFH.
Perspective:
The great majority of persons with LDL-C >190 mg/dl and family history of high cholesterol have polygenic hypercholesterolemia. But it is important to distinguish from HeFH because the latter has a four-fold risk at the same LDL-C. The prevalence of HeFH using genetic testing is about 1:200. It is underdiagnosed, particularly in the United States, where genetic evidence for HeFH is found in up to 15% of persons with premature CAD. Partial penetrance is not uncommon. HeFH can be seen in adults with LDL-C 160-190 mg/dl without the typical phenotype. The classic criteria (Simon Broome and Dutch Lipid Clinic) require tendon xanthomas to conclude definite HeFH and are not commonly found in the statin era.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins
Keywords: Apolipoproteins B, Cholesterol, LDL, Coronary Disease, Dyslipidemias, Genetic Testing, Heterozygote, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, PCSK9 protein, human, Primary Prevention, Proprotein Convertase 9, Xanthomatosis
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