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Molecular and functional characterization of familial chylomicronemia syndrome
Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative...
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| Published in: | Atherosclerosis 2018-02, Vol.269, p.272-278 |
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| creator | Teramoto, Ryota Tada, Hayato Kawashiri, Masa-aki Nohara, Atsushi Nakahashi, Takuya Konno, Tetsuo Inazu, Akihiro Mabuchi, Hiroshi Yamagishi, Masakazu Hayashi, Kenshi |
| description | Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations.
Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency |
| doi_str_mv | 10.1016/j.atherosclerosis.2017.11.006 |
| format | article |
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Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, we used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG.
A total of 1810 variants out of the 73,389 identified with 94.3% mean coverage (×20) were rare and nonsynonymous. Among these, our schema detected four pathogenic or likely pathogenic mutations in the LPL gene (p.Ala248LeufsTer4, p.Arg270Cys, p.Ala361Thr, and p.Val227Gly), including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in the coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed.
These results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis.
•Panel sequencing is also useful in familial chylomicronemia syndrome.•LPL gene was found to be the major driver of this condition.•Hyperchylomicronemia may not be a cause of atherosclerosis.</description><identifier>ISSN: 0021-9150</identifier><identifier>EISSN: 1879-1484</identifier><identifier>DOI: 10.1016/j.atherosclerosis.2017.11.006</identifier><identifier>PMID: 29153744</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Adult ; Child ; Child, Preschool ; Computed Tomography Angiography ; Coronary Angiography - methods ; Coronary Artery Disease - diagnostic imaging ; Coronary Artery Disease - genetics ; Disease Progression ; DNA Mutational Analysis - methods ; Familial chylomicronemia syndrome ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Heredity ; High-Throughput Nucleotide Sequencing ; Humans ; Hyperlipoproteinemia Type I - blood ; Hyperlipoproteinemia Type I - complications ; Hyperlipoproteinemia Type I - diagnosis ; Hyperlipoproteinemia Type I - genetics ; Hypertriglyceridemia - blood ; Hypertriglyceridemia - diagnosis ; Hypertriglyceridemia - genetics ; Infant ; Lipoprotein ; Lipoprotein Lipase - genetics ; Lipoprotein lipase deficiency ; Male ; Mutation ; Pancreatitis - diagnosis ; Pancreatitis - genetics ; Phenotype ; Recurrence ; Risk Factors ; Time Factors ; Triglyceride ; Triglycerides - blood ; Up-Regulation ; Young Adult</subject><ispartof>Atherosclerosis, 2018-02, Vol.269, p.272-278</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-1fa7af904bf01021b44d9beabf4f67ab46877fd5269852bfe479e4d7a4f4bfca3</citedby><cites>FETCH-LOGICAL-c455t-1fa7af904bf01021b44d9beabf4f67ab46877fd5269852bfe479e4d7a4f4bfca3</cites><orcidid>0000-0002-7589-2758</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29153744$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Teramoto, Ryota</creatorcontrib><creatorcontrib>Tada, Hayato</creatorcontrib><creatorcontrib>Kawashiri, Masa-aki</creatorcontrib><creatorcontrib>Nohara, Atsushi</creatorcontrib><creatorcontrib>Nakahashi, Takuya</creatorcontrib><creatorcontrib>Konno, Tetsuo</creatorcontrib><creatorcontrib>Inazu, Akihiro</creatorcontrib><creatorcontrib>Mabuchi, Hiroshi</creatorcontrib><creatorcontrib>Yamagishi, Masakazu</creatorcontrib><creatorcontrib>Hayashi, Kenshi</creatorcontrib><title>Molecular and functional characterization of familial chylomicronemia syndrome</title><title>Atherosclerosis</title><addtitle>Atherosclerosis</addtitle><description>Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations.
Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, we used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG.
A total of 1810 variants out of the 73,389 identified with 94.3% mean coverage (×20) were rare and nonsynonymous. Among these, our schema detected four pathogenic or likely pathogenic mutations in the LPL gene (p.Ala248LeufsTer4, p.Arg270Cys, p.Ala361Thr, and p.Val227Gly), including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in the coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed.
These results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis.
•Panel sequencing is also useful in familial chylomicronemia syndrome.•LPL gene was found to be the major driver of this condition.•Hyperchylomicronemia may not be a cause of atherosclerosis.</description><subject>Adult</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Computed Tomography Angiography</subject><subject>Coronary Angiography - methods</subject><subject>Coronary Artery Disease - diagnostic imaging</subject><subject>Coronary Artery Disease - genetics</subject><subject>Disease Progression</subject><subject>DNA Mutational Analysis - methods</subject><subject>Familial chylomicronemia syndrome</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Genetic Predisposition to Disease</subject><subject>Heredity</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Humans</subject><subject>Hyperlipoproteinemia Type I - blood</subject><subject>Hyperlipoproteinemia Type I - complications</subject><subject>Hyperlipoproteinemia Type I - diagnosis</subject><subject>Hyperlipoproteinemia Type I - genetics</subject><subject>Hypertriglyceridemia - blood</subject><subject>Hypertriglyceridemia - diagnosis</subject><subject>Hypertriglyceridemia - genetics</subject><subject>Infant</subject><subject>Lipoprotein</subject><subject>Lipoprotein Lipase - genetics</subject><subject>Lipoprotein lipase deficiency</subject><subject>Male</subject><subject>Mutation</subject><subject>Pancreatitis - diagnosis</subject><subject>Pancreatitis - genetics</subject><subject>Phenotype</subject><subject>Recurrence</subject><subject>Risk Factors</subject><subject>Time Factors</subject><subject>Triglyceride</subject><subject>Triglycerides - blood</subject><subject>Up-Regulation</subject><subject>Young Adult</subject><issn>0021-9150</issn><issn>1879-1484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqNkD1P5DAQhi3E6Vjg_gJKg0ST4Mk6cVJQIAQLEnfXHLU1ccbCKycGO0Ha-_V4WaCgopmRZt53Ph7GToEXwKE-Xxc4PVLwUbtttLEoOcgCoOC83mMLaGSbg2jEPltwXkLeQsUP2GGMa865kND8ZAdlKi6lEAv257d3pGeHIcOxz8w86sn6EV2mHzGgnijY_7gtZd5kBgfr7Ftz4_xgdfAjDRazuBn74Ac6Zj8Muki_3vMRe7i5_nd1m9__Xd1dXd7nWlTVlINBiablojMc0pGdEH3bEXZGmFpiJ-pGStNXZd02VdkZErIl0UsUJlk0Lo_Y2W7uU_DPM8VJDTZqcg5H8nNU0Na1EGX6MUkvdtJ0bIyBjHoKdsCwUcDVFqlaqy9I1RapAlAJafKfvK-au4H6T_cHwyRY7QSUHn6xFFTUlkZNvQ2kJ9V7-81Vr_0llDs</recordid><startdate>201802</startdate><enddate>201802</enddate><creator>Teramoto, Ryota</creator><creator>Tada, Hayato</creator><creator>Kawashiri, Masa-aki</creator><creator>Nohara, Atsushi</creator><creator>Nakahashi, Takuya</creator><creator>Konno, Tetsuo</creator><creator>Inazu, Akihiro</creator><creator>Mabuchi, Hiroshi</creator><creator>Yamagishi, Masakazu</creator><creator>Hayashi, Kenshi</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7589-2758</orcidid></search><sort><creationdate>201802</creationdate><title>Molecular and functional characterization of familial chylomicronemia syndrome</title><author>Teramoto, Ryota ; Tada, Hayato ; Kawashiri, Masa-aki ; Nohara, Atsushi ; Nakahashi, Takuya ; Konno, Tetsuo ; Inazu, Akihiro ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; Hayashi, Kenshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-1fa7af904bf01021b44d9beabf4f67ab46877fd5269852bfe479e4d7a4f4bfca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Computed Tomography Angiography</topic><topic>Coronary Angiography - methods</topic><topic>Coronary Artery Disease - diagnostic imaging</topic><topic>Coronary Artery Disease - genetics</topic><topic>Disease Progression</topic><topic>DNA Mutational Analysis - methods</topic><topic>Familial chylomicronemia syndrome</topic><topic>Female</topic><topic>Gene Frequency</topic><topic>Genetic Predisposition to Disease</topic><topic>Heredity</topic><topic>High-Throughput Nucleotide Sequencing</topic><topic>Humans</topic><topic>Hyperlipoproteinemia Type I - blood</topic><topic>Hyperlipoproteinemia Type I - complications</topic><topic>Hyperlipoproteinemia Type I - diagnosis</topic><topic>Hyperlipoproteinemia Type I - genetics</topic><topic>Hypertriglyceridemia - blood</topic><topic>Hypertriglyceridemia - diagnosis</topic><topic>Hypertriglyceridemia - genetics</topic><topic>Infant</topic><topic>Lipoprotein</topic><topic>Lipoprotein Lipase - genetics</topic><topic>Lipoprotein lipase deficiency</topic><topic>Male</topic><topic>Mutation</topic><topic>Pancreatitis - diagnosis</topic><topic>Pancreatitis - genetics</topic><topic>Phenotype</topic><topic>Recurrence</topic><topic>Risk Factors</topic><topic>Time Factors</topic><topic>Triglyceride</topic><topic>Triglycerides - blood</topic><topic>Up-Regulation</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Teramoto, Ryota</creatorcontrib><creatorcontrib>Tada, Hayato</creatorcontrib><creatorcontrib>Kawashiri, Masa-aki</creatorcontrib><creatorcontrib>Nohara, Atsushi</creatorcontrib><creatorcontrib>Nakahashi, Takuya</creatorcontrib><creatorcontrib>Konno, Tetsuo</creatorcontrib><creatorcontrib>Inazu, Akihiro</creatorcontrib><creatorcontrib>Mabuchi, Hiroshi</creatorcontrib><creatorcontrib>Yamagishi, Masakazu</creatorcontrib><creatorcontrib>Hayashi, Kenshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Atherosclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Teramoto, Ryota</au><au>Tada, Hayato</au><au>Kawashiri, Masa-aki</au><au>Nohara, Atsushi</au><au>Nakahashi, Takuya</au><au>Konno, Tetsuo</au><au>Inazu, Akihiro</au><au>Mabuchi, Hiroshi</au><au>Yamagishi, Masakazu</au><au>Hayashi, Kenshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular and functional characterization of familial chylomicronemia syndrome</atitle><jtitle>Atherosclerosis</jtitle><addtitle>Atherosclerosis</addtitle><date>2018-02</date><risdate>2018</risdate><volume>269</volume><spage>272</spage><epage>278</epage><pages>272-278</pages><issn>0021-9150</issn><eissn>1879-1484</eissn><abstract>Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations.
Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, we used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG.
A total of 1810 variants out of the 73,389 identified with 94.3% mean coverage (×20) were rare and nonsynonymous. Among these, our schema detected four pathogenic or likely pathogenic mutations in the LPL gene (p.Ala248LeufsTer4, p.Arg270Cys, p.Ala361Thr, and p.Val227Gly), including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in the coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed.
These results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis.
•Panel sequencing is also useful in familial chylomicronemia syndrome.•LPL gene was found to be the major driver of this condition.•Hyperchylomicronemia may not be a cause of atherosclerosis.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>29153744</pmid><doi>10.1016/j.atherosclerosis.2017.11.006</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-7589-2758</orcidid></addata></record> |
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| subjects | Adult Child Child, Preschool Computed Tomography Angiography Coronary Angiography - methods Coronary Artery Disease - diagnostic imaging Coronary Artery Disease - genetics Disease Progression DNA Mutational Analysis - methods Familial chylomicronemia syndrome Female Gene Frequency Genetic Predisposition to Disease Heredity High-Throughput Nucleotide Sequencing Humans Hyperlipoproteinemia Type I - blood Hyperlipoproteinemia Type I - complications Hyperlipoproteinemia Type I - diagnosis Hyperlipoproteinemia Type I - genetics Hypertriglyceridemia - blood Hypertriglyceridemia - diagnosis Hypertriglyceridemia - genetics Infant Lipoprotein Lipoprotein Lipase - genetics Lipoprotein lipase deficiency Male Mutation Pancreatitis - diagnosis Pancreatitis - genetics Phenotype Recurrence Risk Factors Time Factors Triglyceride Triglycerides - blood Up-Regulation Young Adult |
| title | Molecular and functional characterization of familial chylomicronemia syndrome |
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