Large-scale deletions of the ABCA1 gene in patients with hypoalphalipoproteinemia.

Journal of lipid research 2018 Aug

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Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia. Copyright © 2018 Dron et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

Citation

Jacqueline S Dron, Jian Wang, Amanda J Berberich, Michael A Iacocca, Henian Cao, Ping Yang, Joan Knoll, Karine Tremblay, Diane Brisson, Christian Netzer, Ioanna Gouni-Berthold, Daniel Gaudet, Robert A Hegele. Large-scale deletions of the ABCA1 gene in patients with hypoalphalipoproteinemia. Journal of lipid research. 2018 Aug;59(8):1529-1535