Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5′ untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5′UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels. Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5′ untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5′UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels. Elevations in fasting plasma triglyceride (TG) levels are diagnosed as hypertriglyceridemia (HTG). TG levels ≥10 mmol/l (885 mg/dl) are classified as severe HTG (1Hegele R.A. Ginsberg H.N. Chapman M.J. Nordestgaard B.G. Kuivenhoven J.A. Averna M. Boren J. Bruckert E. Catapano A.L. Descamps O.S. et al.The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.Lancet Diabetes Endocrinol. 2014; 2: 655-666Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar) and are seen in ∼1 in 600 individuals (2Dron J.S. Hegele R.A. Genetics of triglycerides and the risk of atherosclerosis.Curr. Atheroscler. Rep. 2017; 19: 31Crossref PubMed Scopus (72) Google Scholar). As a relatively common form of dyslipidemia with serious health complications that include pancreatitis (2Dron J.S. Hegele R.A. Genetics of triglycerides and the risk of atherosclerosis.Curr. Atheroscler. Rep. 2017; 19: 31Crossref PubMed Scopus (72) Google Scholar, 3Brahm A.J. Hegele R.A. Chylomicronaemia–current diagnosis and future therapies.Nat. Rev. Endocrinol. 2015; 11: 352-362Crossref PubMed Scopus (212) Google Scholar), there is a focus on identifying and understanding factors that can increase susceptibility to or cause severe HTG. A combination of rare single-nucleotide variants and common SNPs can contribute permissively or causally toward the presentation of this complex disease (3Brahm A.J. Hegele R.A. Chylomicronaemia–current diagnosis and future therapies.Nat. Rev. Endocrinol. 2015; 11: 352-362Crossref PubMed Scopus (212) Google Scholar). The monogenic form of severe HTG, also referred to as familial chylomicronemia syndrome (FCS), is caused by bi-allelic variants disrupting canonical genes involved in TG metabolism, such as LPL, APOC2, APOA5, glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1), or lipase maturation factor 1 (LMF1) (4Johansen C.T. Kathiresan S. Hegele R.A. Genetic determinants of plasma triglycerides.J. Lipid Res. 2011; 52: 189-206Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Conversely, increased susceptibility for the polygenic form of severe HTG is due to a combination of heterozygous rare variants and common TG-raising alleles at certain SNP loci (5Johansen C.T. Wang J. Lanktree M.B. McIntyre A.D. Ban M.R. Martins R.A. Kennedy B.A. Hassell R.G. Visser M.E. Schwartz S.M. et al.An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.Arterioscler. Thromb. Vasc. Biol. 2011; 31: 1916-1926Crossref PubMed Scopus (74) Google Scholar, 6Johansen C.T. Wang J. McIntyre A.D. Martins R.A. Ban M.R. Lanktree M.B. Huff M.W. Peterfy M. Mehrabian M. Lusis A.J. et al.Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia.Circ Cardiovasc Genet. 2012; 5: 66-72Crossref PubMed Scopus (67) Google Scholar, 7Johansen C.T. Wang J. Lanktree M.B. Cao H. McIntyre A.D. Ban M.R. Martins R.A. Kennedy B.A. Hassell R.G. Visser M.E. et al.Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.Nat. Genet. 2010; 42: 684-687Crossref PubMed Scopus (373) Google Scholar, 8Surendran R.P. Visser M.E. Heemelaar S. Wang J. Peter J. Defesche J.C. Kuivenhoven J.A. Hosseini M. Peterfy M. Kastelein J.J. et al.Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia.J. Intern. Med. 2012; 272: 185-196Crossref PubMed Scopus (180) Google Scholar, 9Kathiresan S. Willer C.J. Peloso G.M. Demissie S. Musunuru K. Schadt E.E. Kaplan L. Bennett D. Li Y. Tanaka T. et al.Common variants at 30 loci contribute to polygenic dyslipidemia.Nat. Genet. 2009; 41: 56-65Crossref PubMed Scopus (1088) Google Scholar, 10Teslovich T.M. Musunuru K. Smith A.V. Edmondson A.C. Stylianou I.M. Koseki M. Pirruccello J.P. Ripatti S. Chasman D.I. Willer C.J. et al.Biological, clinical and population relevance of 95 loci for blood lipids.Nature. 2010; 466: 707-713Crossref PubMed Scopus (2787) Google Scholar, 11Willer C.J. Schmidt E.M. Sengupta S. Peloso G.M. Gustafsson S. Kanoni S. Ganna A. Chen J. Buchkovich M.L. Mora S. et al.Discovery and refinement of loci associated with lipid levels.Nat. Genet. 2013; 45: 1274-1283Crossref PubMed Scopus (1889) Google Scholar, 12Wang J. Ban M.R. Zou G.Y. Cao H. Lin T. Kennedy B.A. Anand S. Yusuf S. Huff M.W. Pollex R.L. et al.Polygenic determinants of severe hypertriglyceridemia.Hum. Mol. Genet. 2008; 17: 2894-2899Crossref PubMed Scopus (108) Google Scholar, 13Dron J.S. Wang J. Cao H. McIntyre A.D. Iacocca M.A. Menard J.R. Movsesyan I. Malloy M.J. Pullinger C.R. Kane J.P. et al.Severe hypertriglyceridemia is primarily polygenic.J. Clin. Lipidol. 2019; 13: 80-88Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Previously, it has been shown that copy-number variants (CNVs) are an additional type of genetic variation that can markedly contribute to extreme perturbations of TG levels (14Langlois S. Deeb S. Brunzell J.D. Kastelein J.J. Hayden M.R. A major insertion accounts for a significant proportion of mutations underlying human lipoprotein lipase deficiency.Proc. Natl. Acad. Sci. USA. 1989; 86: 948-952Crossref PubMed Scopus (81) Google Scholar, 15Devlin R.H. Deeb S. Brunzell J. Hayden M.R. Partial gene duplication involving exon-Alu interchange results in lipoprotein lipase deficiency.Am. J. Hum. Genet. 1990; 46: 112-119PubMed Google Scholar, 16Benlian P. Etienne J. de Gennes J.L. Noe L. Brault D. Raisonnier A. Arnault F. Hamelin J. Foubert L. Chuat J.C. et al.Homozygous deletion of exon 9 causes lipoprotein lipase deficiency: possible intron-Alu recombination.J. Lipid Res. 1995; 36: 356-366Abstract Full Text PDF PubMed Google Scholar, 17Okubo M. Horinishi A. Saito M. Ebara T. Endo Y. Kaku K. Murase T. Eto M. A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency.Mol. Genet. Metab. 2007; 92: 229-233Crossref PubMed Scopus (35) Google Scholar), as well as other lipid traits and disorders (18Iacocca M.A. Hegele R.A. Role of DNA copy number variation in dyslipidemias.Curr. Opin. Lipidol. 2018; 29: 125-132Crossref PubMed Scopus (26) Google Scholar, 19Iacocca M.A. Dron J.S. Hegele R.A. Progress in finding pathogenic DNA copy number variations in dyslipidemia.Curr. Opin. Lipidol. 2019; 30: 63-70Crossref PubMed Scopus (15) Google Scholar, 20Dron J.S. Wang J. Berberich A.J. Iacocca M.A. Cao H. Yang P. Knoll J. Tremblay K. Brisson D. Netzer C. et al.Large-scale deletions of the ABCA1 gene in patients with hypoalphalipoproteinemia.J. Lipid Res. 2018; 59: 1529-1535Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 21Iacocca M.A. Wang J. Sarkar S. Dron J.S. Lagace T. McIntyre A.D. Lau P. Robinson J.F. Yang P. Knoll J.H. et al.Whole-gene duplication of PCSK9 as a novel genetic mechanism for severe familial hypercholesterolemia.Can. J. Cardiol. 2018; 34: 1316-1324Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 22Iacocca M.A. Chora J.R. Carrie A. Freiberger T. Leigh S.E. Defesche J.C. Kurtz C.L. DiStefano M.T. Santos R.D. Humphries S.E. et al.ClinGen FH Variant Curation Expert Panel Clinvar database of global familial hypercholesterolemia-associated DNA variants.Hum. Mutat. 2018; 39: 1631-1640Crossref PubMed Scopus (62) Google Scholar). Assessment of CNVs is becoming easier due to improvements in sequencing technologies and bioinformatic analysis tools (18Iacocca M.A. Hegele R.A. Role of DNA copy number variation in dyslipidemias.Curr. Opin. Lipidol. 2018; 29: 125-132Crossref PubMed Scopus (26) Google Scholar, 23Valsesia A. Mace A. Jacquemont S. Beckmann J.S. Kutalik Z. The growing importance of CNVs: new insights for detection and clinical interpretation.Front. Genet. 2013; 4: 92Crossref PubMed Scopus (40) Google Scholar). Because of this, it is possible to screen for CNVs in patient samples concurrently with rare single-nucleotide variants and SNPs (19Iacocca M.A. Dron J.S. Hegele R.A. Progress in finding pathogenic DNA copy number variations in dyslipidemia.Curr. Opin. Lipidol. 2019; 30: 63-70Crossref PubMed Scopus (15) Google Scholar), and assess them as possible causes or contributors toward severe HTG. A previous study of 563 patients with severe HTG led to the identification of one individual who was likely carrying a heterozygous CNV deletion in LPL (13Dron J.S. Wang J. Cao H. McIntyre A.D. Iacocca M.A. Menard J.R. Movsesyan I. Malloy M.J. Pullinger C.R. Kane J.P. et al.Severe hypertriglyceridemia is primarily polygenic.J. Clin. Lipidol. 2019; 13: 80-88Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). From our next-generation sequencing method and data archive (24Johansen C.T. Dube J.B. Loyzer M.N. MacDonald A. Carter D.E. McIntyre A.D. Cao H. Wang J. Robinson J.F. Hegele R.A. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias.J. Lipid Res. 2014; 55: 765-772Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar), we expanded our search for additional LPL CNVs that might be contributing toward the presentation of severe HTG in a larger cohort of patients. We discovered a total of four out of 632 patients with severe HTG who were heterozygous carriers for one of two novel CNV deletions disrupting LPL. We molecularly confirm and characterize each deletion and discuss their likely contribution to severe HTG. Severe HTG patients (defined as TG ≥10 mmol/l or 885 mg/dl on at least one occasion) from the Lipid Genetics Clinic at the London Health Sciences Centre, University Hospital (London, Ontario, Canada), the Genomic Resource in Arteriosclerosis and Metabolic Disease recruited at the Lipid, Diabetes, or Cardiology Clinics (University of California, San Francisco, CA), or patient samples directly from collaborating research centers were screened for CNVs. Patients provided signed consent with approval from the Western University ethics review board (no. 07290E) or from the originating institution. The study of these patients is in compliance with the principles outlined by Declaration of Helsinki. The genomic DNA from each study subject was isolated and prepared for sequencing following our “LipidSeq” panel design. on our DNA and sequencing method have been in (24Johansen C.T. Dube J.B. Loyzer M.N. MacDonald A. Carter D.E. McIntyre A.D. Cao H. Wang J. Robinson J.F. Hegele R.A. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias.J. Lipid Res. 2014; 55: 765-772Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, J.S. Wang J. C. Robinson J.F. McIntyre A.D. Ban M.R. Cao H. D. Dube et al.Polygenic determinants in of lipoprotein Lipid Res. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). sequencing data was for bioinformatic data were to human and for increased of for each sequencing was as a for each was to for CNV assessment in LPL the The each was the from a of samples that have been confirmed to CNVs. and in a duplication or deletion of genetic The to CNVs has been M.A. Wang J. Dron J.S. Robinson J.F. McIntyre A.D. Cao H. Hegele R.A. of next-generation sequencing to gene copy number variation in familial Lipid Res. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). confirm each we to the likely to the deletions and them for number The and and untranslated region exon 1 and exon were on a for of the Sanger sequencing and of the were to the deletion identifying deletion breakpoints by the spanning the or were for and Sanger sequencing We next-generation sequencing data from a total of 632 individuals with severe HTG. We identified four HTG patients who were carriers for partial deletions in LPL the and of with LPL and other pancreatitis type and TG was mmol/l pancreatitis type genetic exon 1 deletion common LPL polygenic risk exon deletion polygenic risk exon deletion polygenic risk exon deletion polygenic risk provided are from presentation to lipid or in a new provided are from presentation to lipid or 1 was as carrying a heterozygous deletion of the 5′UTR to exon 1. From our the CNV was to a and an of and of 2, and were as carrying a heterozygous deletion of the 5′UTR to exon the of subject CNV was by our this (13Dron J.S. Wang J. Cao H. McIntyre A.D. Iacocca M.A. Menard J.R. Movsesyan I. Malloy M.J. Pullinger C.R. Kane J.P. et al.Severe hypertriglyceridemia is primarily polygenic.J. Clin. Lipidol. 2019; 13: 80-88Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). From our the CNV was to two an of and of an of and of an of and of A combination of and of the CNVs and the deletions and allowed for their The deletion in subject 1 was to be in deletion of LPL, the 5′UTR and exon and of the in 1 2, and were to have the was in deletion of LPL, the exon and exon 2, and of the in We have that these individuals are and breakpoints of LPL exon exon are in the in a new The are in the of 632 patients with severe HTG, four were identified as carriers of one of two partial gene deletions in LPL. CNVs involving LPL, deletions and have been identified methods (14Langlois S. Deeb S. Brunzell J.D. Kastelein J.J. Hayden M.R. A major insertion accounts for a significant proportion of mutations underlying human lipoprotein lipase deficiency.Proc. Natl. Acad. Sci. USA. 1989; 86: 948-952Crossref PubMed Scopus (81) Google Scholar, 15Devlin R.H. Deeb S. Brunzell J. Hayden M.R. Partial gene duplication involving exon-Alu interchange results in lipoprotein lipase deficiency.Am. J. Hum. Genet. 1990; 46: 112-119PubMed Google Scholar, 16Benlian P. Etienne J. de Gennes J.L. Noe L. Brault D. Raisonnier A. Arnault F. Hamelin J. Foubert L. Chuat J.C. et al.Homozygous deletion of exon 9 causes lipoprotein lipase deficiency: possible intron-Alu recombination.J. Lipid Res. 1995; 36: 356-366Abstract Full Text PDF PubMed Google Scholar, 17Okubo M. Horinishi A. Saito M. Ebara T. Endo Y. Kaku K. Murase T. Eto M. A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency.Mol. Genet. Metab. 2007; 92: 229-233Crossref PubMed Scopus (35) Google to our this is one of the identifying and LPL CNVs an bioinformatic with of the genomic A study identified a LPL CNV deletion in an individual with severe HTG methods S. T. S. M. C. S. K. D. et and copy number variations detection in monogenic dyslipidemia a next-generation sequencing Genet. 2018; PubMed Scopus Google Scholar). LPL is the enzyme for the of TG-rich lipoproteins, such as and Role of lipoprotein lipase in lipid Opin. Lipidol. PubMed Scopus Google Scholar, and pathophysiology of and 2013; PubMed Scopus Google Scholar). by LMF1 from to LPL is to the by GPIHBP1 and pathophysiology of and 2013; PubMed Scopus Google Scholar). From LPL to the of TG-rich to the of their TG-rich and pathophysiology of and 2013; PubMed Scopus Google Scholar). that LPL or to an in the of TG-rich there is a increase in the of is the of HTG. that the two identified CNVs spanning the 5′UTR to exon 1 and the 5′UTR to exon the it is certain that these CNVs are null mutations P. P. D. H. of the to a of Full Text Full Text PDF PubMed Scopus (35) Google Scholar). the molecular of these partial gene deletions be confirmed data to protein or protein Because heterozygous deletions were each patient have multifactorial HTG (3Brahm A.J. Hegele R.A. Chylomicronaemia–current diagnosis and future therapies.Nat. Rev. Endocrinol. 2015; 11: 352-362Crossref PubMed Scopus (212) Google Scholar, 12Wang J. Ban M.R. Zou G.Y. Cao H. Lin T. Kennedy B.A. Anand S. Yusuf S. Huff M.W. Pollex R.L. et al.Polygenic determinants of severe hypertriglyceridemia.Hum. Mol. Genet. 2008; 17: 2894-2899Crossref PubMed Scopus (108) Google Scholar, 13Dron J.S. Wang J. Cao H. McIntyre A.D. Iacocca M.A. Menard J.R. Movsesyan I. Malloy M.J. Pullinger C.R. Kane J.P. et al.Severe hypertriglyceridemia is primarily polygenic.J. Clin. Lipidol. 2019; 13: 80-88Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) with additional genetic or or contributing to their clinical phenotype M. in dyslipidemia.Curr. Opin. Lipidol. 2015; PubMed Scopus Google Scholar). polygenic and factors this can be referred to as or chylomicronemia of these patients have a high polygenic risk or other rare variants in canonical TG metabolism the of the CNVs are and the TG levels are these patients are to have to a individuals with bi-allelic variants disrupting one of the canonical TG metabolism genes can be diagnosed with our these LPL CNV deletions have been on LPL CNVs have been et (14Langlois S. Deeb S. Brunzell J.D. Kastelein J.J. Hayden M.R. A major insertion accounts for a significant proportion of mutations underlying human lipoprotein lipase deficiency.Proc. Natl. Acad. Sci. USA. 1989; 86: 948-952Crossref PubMed Scopus (81) Google Scholar) identified individuals with a insertion or a deletion in LPL The et R.H. Deeb S. Brunzell J. Hayden M.R. Partial gene duplication involving exon-Alu interchange results in lipoprotein lipase deficiency.Am. J. Hum. Genet. 1990; 46: 112-119PubMed Google Scholar) the insertion and that it was a duplication disrupting exon of LPL. the of a CNV deletion in LPL was by et P. Etienne J. de Gennes J.L. Noe L. Brault D. Raisonnier A. Arnault F. Hamelin J. Foubert L. Chuat J.C. et al.Homozygous deletion of exon 9 causes lipoprotein lipase deficiency: possible intron-Alu recombination.J. Lipid Res. 1995; 36: 356-366Abstract Full Text PDF PubMed Google Scholar) who a to a deletion exon 9 and in a patient with LPL The on a LPL CNV was more than a et M. Horinishi A. Saito M. Ebara T. Endo Y. Kaku K. Murase T. Eto M. A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency.Mol. Genet. Metab. 2007; 92: 229-233Crossref PubMed Scopus (35) Google Scholar) a complex deletion-insertion analysis and their was a for a deletion exon and insertion at the M. Horinishi A. Saito M. Ebara T. Endo Y. Kaku K. Murase T. Eto M. A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency.Mol. Genet. Metab. 2007; 92: 229-233Crossref PubMed Scopus (35) Google Scholar). more detection a study by et S. T. S. M. C. S. K. D. et and copy number variations detection in monogenic dyslipidemia a next-generation sequencing Genet. 2018; PubMed Scopus Google Scholar) identified a heterozygous LPL deletion of to in a patient with severe HTG this individual also carried a heterozygous single-nucleotide in LPL and was classified as bi-allelic mutations and the of LPL it was to the deletion in of our who have Because their deletion breakpoints are identical by it is possible that these individuals have a common who carried the these patients in is that the CNV in each patient this there is and the the of and CNV J.R. S.M. of in gene copy Rev. Genet. 2009; PubMed Scopus Google Scholar). that CNV the of this LPL deletion in the and suggests that this CNV is more likely by a common than a TG levels in these we that subject 1 who the CNV also the at mmol/l to who the larger CNV TG mmol/l mg/dl) and mmol/l is as to CNV to in TG or it for the of the protein the patients from to and with a of and of pancreatitis 1 and each pancreatitis has been a more individuals with the monogenic form of severe HTG M. S. Hegele R.A. A. familial chylomicronemia syndrome and multifactorial 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). We that these predicted null mutations may have them to relatively higher TG levels than other of genetic and larger it is to the in have been with CNVs underlying in the genetic variants were in individuals with lipid J.S. Wang J. Berberich A.J. Iacocca M.A. Cao H. Yang P. Knoll J. Tremblay K. Brisson D. Netzer C. et al.Large-scale deletions of the ABCA1 gene in patients with hypoalphalipoproteinemia.J. Lipid Res. 2018; 59: 1529-1535Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, Hayden M.R. on a rare and common variants in ABCA1 and their on levels and Rev. PubMed Scopus Google Scholar). The including such as are likely contributing toward the of these HTG in may to the of pancreatitis in these As a heterozygous is to cause that the patients have additional genetic factors identified as contributing toward their these factors be as likely are to characterize the of our identified CNVs on LPL and TG it is also to screen for CNVs in the other canonical TG metabolism such as GPIHBP1 and APOC2, as CNVs in these genes have been identified in individuals with HTG J. C. A. 1 in a with deletion Clin. Lipidol. Full Text Full Text PDF PubMed Scopus Google Scholar, R.A. Berberich A.J. Ban M.R. Wang J. A. L. M. A. Bruckert E. et and of molecular of familial Clin. Lipidol. 2018; Full Text Full Text PDF PubMed Scopus (81) Google Scholar, J.J. S. J. A. A. J.C. of GPIHBP1 severe Metab. 2012; PubMed Scopus Google Scholar). are relatively LPL CNVs are an type of genetic variation that should be screened for the genetic of HTG, their and improvements to next-generation sequencing and more CNV detection CNV assessment can be of rare single-nucleotide variants and polygenic risk (18Iacocca M.A. Hegele R.A. Role of DNA copy number variation in dyslipidemias.Curr. Opin. Lipidol. 2018; 29: 125-132Crossref PubMed Scopus (26) Google Scholar, 19Iacocca M.A. Dron J.S. Hegele R.A. Progress in finding pathogenic DNA copy number variations in dyslipidemia.Curr. Opin. Lipidol. 2019; 30: 63-70Crossref PubMed Scopus (15) Google Scholar). be to characterize including single-nucleotide and the of a larger spectrum of genetic we can a more understanding of the genetic underlying severe HTG. The to and the patients involved in this with copy-number familial chylomicronemia syndrome glycosylphosphatidylinositol-anchored HDL-binding protein 1 hypertriglyceridemia lipase maturation factor 1 next-generation sequencing triglyceride untranslated region

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