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-numb...
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doaj-cdf329801bed4b7895839adade6cadb72021-04-29T04:35:31ZengElsevierJournal of Lipid Research0022-22752019-11-01601119531958Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemiaJacqueline S. Dron0Jian Wang1Adam D. McIntyre2Henian Cao3John F. Robinson4P. Barton Duell5Priya Manjoo6James Feng7Irina Movsesyan8Mary J. Malloy9Clive R. Pullinger10John P. Kane11Robert A. Hegele12Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, Canada; Departments of Biochemistry Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, CanadaRobarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, CanadaRobarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, CanadaRobarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, CanadaRobarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, CanadaKnight Cardiovascular Institute, Oregon Health and Science University, Portland, OR 97239Department of Medicine, Gordon and Leslie Diamond Centre, University of British Columbia, Vancouver, BC V5Z 1M9, CanadaCardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, Canada; Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, Canada; To whom correspondence should be addressed.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.http://www.sciencedirect.com/science/article/pii/S0022227520322938bioinformatic analysisdiagnostic toolsdyslipidemiasgenetic testinghuman geneticsnext-generation sequencing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jacqueline S. Dron Jian Wang Adam D. McIntyre Henian Cao John F. Robinson P. Barton Duell Priya Manjoo James Feng Irina Movsesyan Mary J. Malloy Clive R. Pullinger John P. Kane Robert A. Hegele |
spellingShingle |
Jacqueline S. Dron Jian Wang Adam D. McIntyre Henian Cao John F. Robinson P. Barton Duell Priya Manjoo James Feng Irina Movsesyan Mary J. Malloy Clive R. Pullinger John P. Kane Robert A. Hegele Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia Journal of Lipid Research bioinformatic analysis diagnostic tools dyslipidemias genetic testing human genetics next-generation sequencing |
author_facet |
Jacqueline S. Dron Jian Wang Adam D. McIntyre Henian Cao John F. Robinson P. Barton Duell Priya Manjoo James Feng Irina Movsesyan Mary J. Malloy Clive R. Pullinger John P. Kane Robert A. Hegele |
author_sort |
Jacqueline S. Dron |
title |
Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia |
title_short |
Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia |
title_full |
Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia |
title_fullStr |
Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia |
title_full_unstemmed |
Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia |
title_sort |
partial lpl deletions: rare copy-number variants contributing towards severe hypertriglyceridemia |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2019-11-01 |
description |
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. |
topic |
bioinformatic analysis diagnostic tools dyslipidemias genetic testing human genetics next-generation sequencing |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520322938 |
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