Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading...

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Veröffentlicht in:Gene 2015-07, Vol.565 (1), p.76-84
Hauptverfasser: Al-Allaf, Faisal A., Athar, Mohammad, Abduljaleel, Zainularifeen, Taher, Mohiuddin M., Khan, Wajahatullah, Ba-hammam, Faisal A., Abalkhail, Hala, Alashwal, Abdullah
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container_start_page 76
container_title Gene
container_volume 565
creator Al-Allaf, Faisal A.
Athar, Mohammad
Abduljaleel, Zainularifeen
Taher, Mohiuddin M.
Khan, Wajahatullah
Ba-hammam, Faisal A.
Abalkhail, Hala
Alashwal, Abdullah
description Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. Sequencing whole genome for screening variants for FH are not suitable due to high cost. Hence, in this study we performed targeted customized sequencing of FH 12 genes (Ldlr, ApoB, Pcsk9, Abca1, Apoa2, Apoc3, Apon2, Arh, Ldlrap1, Apoc2, ApoE, and Lpl) that have been implicated in the homozygous phenotype of a proband pedigree to identify candidate variants by NGS Ion torrent PGM. Only three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH based on the variant rate. The results showed that seven deleterious variants in Ldlr, ApoB, and Pcsk9 genes were pathological and were clinically significant based on predictions identified by SIFT and PolyPhen. Targeted customized sequencing is an efficient technique for screening variants among targeted FH genes. Final validation of seven deleterious variants conducted by capillary resulted to only one novel variant in Ldlr gene that was found in exon 14 (c.2026delG, p. Gly676fs). The variant found in Ldlr gene was a novel heterozygous variant derived from a male in the proband. •FH associated 12 gene variants have been identified using NGS Ion torrent PGM.•FH variants in Ldlr, ApoB and Pcsk9 genes resulted in high levels of LDL-C.•Three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH.•Deleterious seven variants were pathologically and were clinically significant.•Deleterious seven variants conducted by capillary showed one variant novel in the Ldlr gene.
doi_str_mv 10.1016/j.gene.2015.03.064
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It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. Sequencing whole genome for screening variants for FH are not suitable due to high cost. Hence, in this study we performed targeted customized sequencing of FH 12 genes (Ldlr, ApoB, Pcsk9, Abca1, Apoa2, Apoc3, Apon2, Arh, Ldlrap1, Apoc2, ApoE, and Lpl) that have been implicated in the homozygous phenotype of a proband pedigree to identify candidate variants by NGS Ion torrent PGM. Only three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH based on the variant rate. The results showed that seven deleterious variants in Ldlr, ApoB, and Pcsk9 genes were pathological and were clinically significant based on predictions identified by SIFT and PolyPhen. Targeted customized sequencing is an efficient technique for screening variants among targeted FH genes. Final validation of seven deleterious variants conducted by capillary resulted to only one novel variant in Ldlr gene that was found in exon 14 (c.2026delG, p. Gly676fs). The variant found in Ldlr gene was a novel heterozygous variant derived from a male in the proband. •FH associated 12 gene variants have been identified using NGS Ion torrent PGM.•FH variants in Ldlr, ApoB and Pcsk9 genes resulted in high levels of LDL-C.•Three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH.•Deleterious seven variants were pathologically and were clinically significant.•Deleterious seven variants conducted by capillary showed one variant novel in the Ldlr gene.</description><identifier>ISSN: 0378-1119</identifier><identifier>EISSN: 1879-0038</identifier><identifier>DOI: 10.1016/j.gene.2015.03.064</identifier><identifier>PMID: 25839937</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Apolipoprotein B-100 - genetics ; Coronary Disease - etiology ; Coronary Disease - genetics ; Coronary heart disease (CHD) ; Familial hypercholesterolemia (FH) ; Female ; Functional changes ; Genetic Variation ; High-Throughput Nucleotide Sequencing ; Humans ; Hyperlipoproteinemia Type II - complications ; Hyperlipoproteinemia Type II - genetics ; LDLR ; Low-density lipoprotein cholesterol (LDLc) ; Male ; Pedigree ; Proprotein Convertase 9 ; Proprotein Convertases - genetics ; Receptors, LDL - genetics ; Sequence Analysis, DNA ; Serine Endopeptidases - genetics</subject><ispartof>Gene, 2015-07, Vol.565 (1), p.76-84</ispartof><rights>2015 Elsevier B.V.</rights><rights>Copyright © 2015 Elsevier B.V. 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It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. Sequencing whole genome for screening variants for FH are not suitable due to high cost. Hence, in this study we performed targeted customized sequencing of FH 12 genes (Ldlr, ApoB, Pcsk9, Abca1, Apoa2, Apoc3, Apon2, Arh, Ldlrap1, Apoc2, ApoE, and Lpl) that have been implicated in the homozygous phenotype of a proband pedigree to identify candidate variants by NGS Ion torrent PGM. Only three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH based on the variant rate. The results showed that seven deleterious variants in Ldlr, ApoB, and Pcsk9 genes were pathological and were clinically significant based on predictions identified by SIFT and PolyPhen. Targeted customized sequencing is an efficient technique for screening variants among targeted FH genes. Final validation of seven deleterious variants conducted by capillary resulted to only one novel variant in Ldlr gene that was found in exon 14 (c.2026delG, p. Gly676fs). The variant found in Ldlr gene was a novel heterozygous variant derived from a male in the proband. •FH associated 12 gene variants have been identified using NGS Ion torrent PGM.•FH variants in Ldlr, ApoB and Pcsk9 genes resulted in high levels of LDL-C.•Three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH.•Deleterious seven variants were pathologically and were clinically significant.•Deleterious seven variants conducted by capillary showed one variant novel in the Ldlr gene.</description><subject>Apolipoprotein B-100 - genetics</subject><subject>Coronary Disease - etiology</subject><subject>Coronary Disease - genetics</subject><subject>Coronary heart disease (CHD)</subject><subject>Familial hypercholesterolemia (FH)</subject><subject>Female</subject><subject>Functional changes</subject><subject>Genetic Variation</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Humans</subject><subject>Hyperlipoproteinemia Type II - complications</subject><subject>Hyperlipoproteinemia Type II - genetics</subject><subject>LDLR</subject><subject>Low-density lipoprotein cholesterol (LDLc)</subject><subject>Male</subject><subject>Pedigree</subject><subject>Proprotein Convertase 9</subject><subject>Proprotein Convertases - genetics</subject><subject>Receptors, LDL - genetics</subject><subject>Sequence Analysis, DNA</subject><subject>Serine Endopeptidases - genetics</subject><issn>0378-1119</issn><issn>1879-0038</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEUhUcIRNPCC7BAXrJJ8M_M2JbYoKr8SBVsYG059p3mhhk72J6UvBcPiIcUluDNle3vHOme0zQvGN0wyvrX-80dBNhwyroNFRvat4-aFVNSrykV6nGzokKqNWNMXzSXOe9pPV3HnzYXvFNCayFXzc9P8KOQxSfZgjGQDN9nCA7DHSmRoIdQcDiREI8w_uYKOnK0CW0omTg756o7AokDsXOJOU52JD5OGCpABjvhiPVldzpAcrs4Qi6Q6pjQEptzdGgLeHKPZUcwuAQ212vC_G2xdDHFYNOJ7MCmQjzm5f9Z82SwY4bnD_Oq-fru5sv1h_Xt5_cfr9_erl3b6bJWWyu0H3rVwSA7JjSVvZfWec6E1VvONLDOuZZ3nG9bxXTrPZUS2lZ4UAMTV82rs-8hxZpKLmbC7GAcbYA4Z8Ok4IpxLej_0V5KpSSTXUX5GXUp5pxgMIeEU13SMGqWYs3eLEGbpVhDhanFVtHLB_95O4H_K_nTZAXenAGogRwRkskOa5HgMYErxkf8l_8vE3W5sw</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Al-Allaf, Faisal A.</creator><creator>Athar, Mohammad</creator><creator>Abduljaleel, Zainularifeen</creator><creator>Taher, Mohiuddin M.</creator><creator>Khan, Wajahatullah</creator><creator>Ba-hammam, Faisal A.</creator><creator>Abalkhail, Hala</creator><creator>Alashwal, Abdullah</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><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20150701</creationdate><title>Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease</title><author>Al-Allaf, Faisal A. ; Athar, Mohammad ; Abduljaleel, Zainularifeen ; Taher, Mohiuddin M. ; Khan, Wajahatullah ; Ba-hammam, Faisal A. ; Abalkhail, Hala ; Alashwal, Abdullah</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-8ba39df685ef75139076d7acd213a9b219e15cc42522b48194dd077e443de8f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Apolipoprotein B-100 - genetics</topic><topic>Coronary Disease - etiology</topic><topic>Coronary Disease - genetics</topic><topic>Coronary heart disease (CHD)</topic><topic>Familial hypercholesterolemia (FH)</topic><topic>Female</topic><topic>Functional changes</topic><topic>Genetic Variation</topic><topic>High-Throughput Nucleotide Sequencing</topic><topic>Humans</topic><topic>Hyperlipoproteinemia Type II - complications</topic><topic>Hyperlipoproteinemia Type II - genetics</topic><topic>LDLR</topic><topic>Low-density lipoprotein cholesterol (LDLc)</topic><topic>Male</topic><topic>Pedigree</topic><topic>Proprotein Convertase 9</topic><topic>Proprotein Convertases - genetics</topic><topic>Receptors, LDL - genetics</topic><topic>Sequence Analysis, DNA</topic><topic>Serine Endopeptidases - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Al-Allaf, Faisal A.</creatorcontrib><creatorcontrib>Athar, Mohammad</creatorcontrib><creatorcontrib>Abduljaleel, Zainularifeen</creatorcontrib><creatorcontrib>Taher, Mohiuddin M.</creatorcontrib><creatorcontrib>Khan, Wajahatullah</creatorcontrib><creatorcontrib>Ba-hammam, Faisal A.</creatorcontrib><creatorcontrib>Abalkhail, Hala</creatorcontrib><creatorcontrib>Alashwal, Abdullah</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><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Gene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Al-Allaf, Faisal A.</au><au>Athar, Mohammad</au><au>Abduljaleel, Zainularifeen</au><au>Taher, Mohiuddin M.</au><au>Khan, Wajahatullah</au><au>Ba-hammam, Faisal A.</au><au>Abalkhail, Hala</au><au>Alashwal, Abdullah</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease</atitle><jtitle>Gene</jtitle><addtitle>Gene</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>565</volume><issue>1</issue><spage>76</spage><epage>84</epage><pages>76-84</pages><issn>0378-1119</issn><eissn>1879-0038</eissn><abstract>Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. Sequencing whole genome for screening variants for FH are not suitable due to high cost. Hence, in this study we performed targeted customized sequencing of FH 12 genes (Ldlr, ApoB, Pcsk9, Abca1, Apoa2, Apoc3, Apon2, Arh, Ldlrap1, Apoc2, ApoE, and Lpl) that have been implicated in the homozygous phenotype of a proband pedigree to identify candidate variants by NGS Ion torrent PGM. Only three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH based on the variant rate. The results showed that seven deleterious variants in Ldlr, ApoB, and Pcsk9 genes were pathological and were clinically significant based on predictions identified by SIFT and PolyPhen. Targeted customized sequencing is an efficient technique for screening variants among targeted FH genes. Final validation of seven deleterious variants conducted by capillary resulted to only one novel variant in Ldlr gene that was found in exon 14 (c.2026delG, p. Gly676fs). The variant found in Ldlr gene was a novel heterozygous variant derived from a male in the proband. •FH associated 12 gene variants have been identified using NGS Ion torrent PGM.•FH variants in Ldlr, ApoB and Pcsk9 genes resulted in high levels of LDL-C.•Three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH.•Deleterious seven variants were pathologically and were clinically significant.•Deleterious seven variants conducted by capillary showed one variant novel in the Ldlr gene.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>25839937</pmid><doi>10.1016/j.gene.2015.03.064</doi><tpages>9</tpages></addata></record>
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subjects Apolipoprotein B-100 - genetics
Coronary Disease - etiology
Coronary Disease - genetics
Coronary heart disease (CHD)
Familial hypercholesterolemia (FH)
Female
Functional changes
Genetic Variation
High-Throughput Nucleotide Sequencing
Humans
Hyperlipoproteinemia Type II - complications
Hyperlipoproteinemia Type II - genetics
LDLR
Low-density lipoprotein cholesterol (LDLc)
Male
Pedigree
Proprotein Convertase 9
Proprotein Convertases - genetics
Receptors, LDL - genetics
Sequence Analysis, DNA
Serine Endopeptidases - genetics
title Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease
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