Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort




Garg, Abhimanyu
Fazio, Sergio
Duell, P. Barton
Baass, Alexis
Udata, Chandrasekhar
Joh, Tenshang
Riel, Tom
Sirota, Marina
Dettling, Danielle
Liang, Hong

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BACKGROUND: Familial hypercholesterolemia (FH) confers a very high risk of premature cardiovascular disease and is commonly caused by mutations in LDLR, APOB, or PCSK9 and very rarely in LDLRAP1. OBJECTIVE: To determine the prevalence of pathogenic mutations in the LDLR, APOB, and PCSK9 in a cohort of subjects who met Simon Broome criteria for FH, and compare the clinical characteristics of mutation-positive and –negative subjects. METHODS: 93 men and 107 women aged 19–80 years from lipid clinics in the United States and Canada participated. Demographic and historical data were collected, physical examination performed, and serum lipids/lipoproteins analyzed. Targeted sequencing analyses of LDLR and PCSK9 coding regions and exon 26 of APOB were performed, followed by detection of LDLR deletions and duplications. RESULTS: Disease-causing LDLR and APOB variants were identified in 114 and 6 subjects, respectively. Of the 58 LDLR variants, 8 were novel mutations. Compared with mutation-positive subjects, mutation-negative subjects were older (mean: 49 years versus 57 years, respectively) and had a higher proportion of African-Americans (1% versus 12.5%), higher prevalence of hypertension (21% versus 46%), and higher serum triglycerides (median: 86 mg/dL versus 122 mg/dL) levels. CONCLUSION: LDLR mutations were the most common cause of heterozygous FH in this North American cohort. A strikingly high proportion of FH subjects (40%) lacked mutations in known culprit genes. Identification of underlying genetic and environmental factors in mutation-negative patients is important to further our understanding of the metabolic basis of FH and other forms of severe hypercholesterolemia.

General Notes

Genotyping of 200 adults with clinical diagnosis of familial hypercholesterolemia from North America revealed that 40 percent of them had no disease-causing variants in LDLR, PCSK9 and APOB genes.
This submission meets the Extended Data Sets and Supplemental Materials requirements that are included in author guidelines for Journal of Clinical Endocrinology and Metabolism (Print ISSN 0021-972X, Online ISSN 1945-7197).

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Garg A, Fazio S, Duell PB, Baass A, Udata C, Joh T, Riel T, Sirota M, Dettling D, Liang H, Garzone PD, Gumbiner B, Wan H. Data from: Molecular characterization of familial hypercholesterolemia in a North American cohort. UT Southwestern Institutional Repository 2019. Deposited 7 June 2019.

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