Abstract 18320: A Novel Tandem Duplication Containing a Noncoding Exon of the APOC2 Gene Causes Chylomicronemia With Markedly Reduced Levels of Plasma Apolipoprotein C-II
Introduction: Apolipoprotein C -II (apoC-II) promotes hydrolysis of triglycerides (TG) in TG-rich lipoproteins as a cofactor of lipoprotein lipase (LPL), and apoC-II deficiency, mostly caused by mutations in the coding regions of APOC2, leads to severe hypertriglyceridemia (HTG). In several atypical cases, mutations in the promoter region or a splice site of APOC2 cause markedly reduced, but detectable levels of plasma apoC-II as well as massive HTG (hereafter referred to as hypoapoC-II). Previously, we reported a case of hypoapoC -II with severe HTG (Case 1), in which no rare variant was identified in the coding regions of APOC2; however, the clinical entity of hypoapoC-II still remains controversial because evidence of causality is weak with only sporadic cases reported.
Aim: The aim of this study is to explore the molecular basis of hypoapoC -II by analyzing Case 1 and two additional cases of hypoapoC-II.
Methods: Case 1 and two new cases (Cases 2 and 3) of hypoapoC -II were analyzed. Whole genome/exome sequencing was performed using Ilumina HiSeq2000/2500. Southern blot hybridization analysis was performed using APOC2 or APOC4 cDNA probes. Breakpoint was analyzed by amplifying the breakpoint region by PCR, followed by subcloning and direct nucleotide sequencing analysis. Custom-made array CGH analysis was performed using probe sets around the APOE/APOC4/APOC2 gene cluster. Haplotype analysis was performed after SNPs were genotyped by microarray.
Results: Whole genome sequencing of Case 1 revealed a two-fold increase in coverage in the region containing APOC4 and a noncoding exon of APOC2. Array CGH analysis, Southern blot hybridization analysis, and breakpoint analysis confirmed that the region was homozygous tandem duplication. Surprisingly, Case 2 harbors the same tandem duplication as Case 1 as revealed by array CGH and breakpoint analysis. Although cases 1 and 2 were apparently unrelated, haplotype analysis uncovered a founder haplotype spanning 680 kb.
Conclusions: We found two independent cases of hypoapoC-II harboring the same tandem duplication containing APOC4 and a noncoding exon of APOC2 with founder haplotype. Our cases represent a distinct clinical subtype of hyperchylomicronemia with markedly reduced levels of apoC-II.
Author Disclosures: S. Takase: None. H. Ishiura: None. M. Kurano: None. J. Mitsui: None. M. Takanashi: None. Y. Taira: None. T. Kimura: None. S. Okazaki: None. Y. Iizuka: None. H. Yoshida: None. N. Tada: None. J. Osuga: None. F. Sawano: None. M. Hara: None. K. Tsukamoto: None. S. Tsuji: None. S. Ishibashi: None. T. Kadowaki: None. H. Okazaki: None.
- © 2016 by American Heart Association, Inc.