Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia Michael A. Iacocca, BSc, Jian Wang, MD, Samantha.

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Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia Michael A. Iacocca, BSc, Jian Wang, MD, Samantha Sarkar, BSc, Jacqueline S. Dron, BSc, Thomas Lagace, PhD, Adam D. McIntyre, BSc, Paulina Lau, MSc, John F. Robinson, BSc, Ping Yang, PhD, Joan H. Knoll, PhD, Henian Cao, MD, PhD, Ruth McPherson, MD, PhD, Robert A. Hegele, MD, FRCPC, FACP Canadian Journal of Cardiology Volume 34, Issue 10, Pages 1316-1324 (October 2018) DOI: 10.1016/j.cjca.2018.07.479 Copyright © 2018 The Authors Terms and Conditions

Figure 1 Next-generation sequencing (NGS)-based detection of a PCSK9 copy number variation (CNV) in a patient with familial hypercholesterolemia (index case A). (A) Targeted NGS output: duplication of all 12 exons of the PCSK9 gene, plus rs11206510 probe 8655 bases upstream of PCSK9. Different regions of the output are as follows: (i) Normalized ratio metric computed for each NGS probe target region in PCSK9; depth of sequence coverage comparative to reference controls. (ii) Normalized z-score metric; number of standard deviations the depth of coverage is from the reference control mean coverage. (iii) Called CNV state per probe target region, determined by ratio and z-score metrics together with supporting evidence from variant allele frequencies (not shown). (iv) Multiple affected target regions merged by segmentation analysis to call a contiguous duplication event. (v) Exon map of the PCSK9 gene. (vi) LipidSeq probe target regions. (B) Whole-exome sequencing (WES) output: validation of PCSK9 whole-gene duplication, plus flanking genes BSND (5′) and USP24 (3′) unaffected (diploid). Panel regions (i)-(iv) are as in (A). (v) Exon map of PCSK9 and flanking genes. (vi) WES probe target regions. Canadian Journal of Cardiology 2018 34, 1316-1324DOI: (10.1016/j.cjca.2018.07.479) Copyright © 2018 The Authors Terms and Conditions

Figure 2 Next-generation sequencing (NGS)-based detection of a PCSK9 copy number variation in a patient with familial hypercholesterolemia (index case B). (A) Targeted NGS output: duplication of all 12 exons of the PCSK9 gene, plus rs11206510 probe 8655 bases upstream of PCSK9. (B) Whole-exome sequencing output: validation of PCSK9 whole-gene duplication, plus flanking genes BSND (5′) and USP24 (3′) unaffected (diploid). All panel regions are as in Fig. 1. Canadian Journal of Cardiology 2018 34, 1316-1324DOI: (10.1016/j.cjca.2018.07.479) Copyright © 2018 The Authors Terms and Conditions

Figure 3 Family pedigree of 2 familial hypercholesterolemia index cases with a whole-gene duplication of PCSK9. Males and females are represented as squares and circles, respectively, whereas black-shaded and unshaded represent individuals with reported severe hypercholesterolemia and normal lipid profiles, respectively. Enlarged shapes refer to individuals where a DNA sample was possible to obtain and analyse for the presence (+) or absence (−) of a PCSK9 copy number variation (CNV). Grey diagonal lines indicate deceased. Roman numerals I-IV indicate generation. CABG, coronary arterial bypass graft; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; TC, total cholesterol. Canadian Journal of Cardiology 2018 34, 1316-1324DOI: (10.1016/j.cjca.2018.07.479) Copyright © 2018 The Authors Terms and Conditions

Figure 4 Plasma PCSK9 level in a patient with familial hypercholesterolemia (FH) (index case A) with a PCSK9 whole-gene duplication. (A) Plasma PCSK9 enzyme-linked immunosorbent assay measurement (repeat n = 3). (B) Plasma PCSK9 immunoprecipitation. PCSK9 was immunoprecipitated from ethylenediaminetetraacetic acid (EDTA) plasma using a rabbit polyclonal antibody raised against full-length recombinant human PCSK9 and detected with a monoclonal antibody (15A6). For comparison with normolipidemic control, plasma from a patient with FH (index case A) was diluted 5-fold before immunoprecipitation analysis. Canadian Journal of Cardiology 2018 34, 1316-1324DOI: (10.1016/j.cjca.2018.07.479) Copyright © 2018 The Authors Terms and Conditions