Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia
Idiopathic ventricular tachycardia (IVT) is the major cause of sudden cardiac death. Patients with IVT were usually manifested without structural heart disease. In this present study, we performed family-based whole genome sequencing (WGS) and Sanger sequencing for a 5-year-old Chinese boy with IVT...
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Veröffentlicht in: | Pediatric cardiology 2020-12, Vol.41 (8), p.1783-1794 |
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creator | Du, Zhanhui Kuang, Shan Li, Yong Han, Peng Liu, Junnian Wang, Zhiwei Huang, Yingping Guan, Yuanning Xu, Xun Liu, Xin Banerjee, Santasree Pan, Silin |
description | Idiopathic ventricular tachycardia (IVT) is the major cause of sudden cardiac death. Patients with IVT were usually manifested without structural heart disease. In this present study, we performed family-based whole genome sequencing (WGS) and Sanger sequencing for a 5-year-old Chinese boy with IVT and all the unaffected family members in order to identify the candidate gene and disease-causing mutation underlying the disease phenotype. Results showed that a novel heterozygous single-nucleotide duplication (c.128dup) and a novel heterozygous missense (c.3328A > G) variant in ABCA5 gene were identified in the proband. The single-nucleotide duplication (c.128dupT), inherited from his father and patrilineal grandfather, leads to a frameshift which results into the formation of a truncated ABCA5 protein of 50 (p.Leu43Phefs*8) amino acids. Hence, it is a loss-of-function mutation. The missense (c.3328A > G) variant, inherited from his mother, leads to the replacement of isoleucine by valine at the position of 1110 (p.Ile1110Val) of the ABCA5 protein. Multiple sequence alignment showed that p.Ile1110 is evolutionarily conserved among several species indicating both the structural and functional significance of the p.Ile1110 residue in the wild-type ABCA5 protein. Quantitative RT-PCR showed that the ABCA5 mRNA expression levels were decreased in the proband. These two novel variants of ABCA5 gene were co-segregated well among all the members of this family. Our present study also strongly supports the importance of using family-based whole genome sequencing for identifying novel candidate genes associated with IVT. |
doi_str_mv | 10.1007/s00246-020-02446-4 |
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Patients with IVT were usually manifested without structural heart disease. In this present study, we performed family-based whole genome sequencing (WGS) and Sanger sequencing for a 5-year-old Chinese boy with IVT and all the unaffected family members in order to identify the candidate gene and disease-causing mutation underlying the disease phenotype. Results showed that a novel heterozygous single-nucleotide duplication (c.128dup) and a novel heterozygous missense (c.3328A > G) variant in ABCA5 gene were identified in the proband. The single-nucleotide duplication (c.128dupT), inherited from his father and patrilineal grandfather, leads to a frameshift which results into the formation of a truncated ABCA5 protein of 50 (p.Leu43Phefs*8) amino acids. Hence, it is a loss-of-function mutation. The missense (c.3328A > G) variant, inherited from his mother, leads to the replacement of isoleucine by valine at the position of 1110 (p.Ile1110Val) of the ABCA5 protein. Multiple sequence alignment showed that p.Ile1110 is evolutionarily conserved among several species indicating both the structural and functional significance of the p.Ile1110 residue in the wild-type ABCA5 protein. Quantitative RT-PCR showed that the ABCA5 mRNA expression levels were decreased in the proband. These two novel variants of ABCA5 gene were co-segregated well among all the members of this family. Our present study also strongly supports the importance of using family-based whole genome sequencing for identifying novel candidate genes associated with IVT.</description><identifier>ISSN: 0172-0643</identifier><identifier>EISSN: 1432-1971</identifier><identifier>DOI: 10.1007/s00246-020-02446-4</identifier><identifier>PMID: 32939586</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Asian Continental Ancestry Group - genetics ; ATP-Binding Cassette Transporters - genetics ; Cardiac Surgery ; Cardiology ; Child, Preschool ; Death, Sudden, Cardiac - epidemiology ; DNA sequencing ; Genes ; Genetic aspects ; Genomes ; Genomics ; Heart ; Heart diseases ; Heterozygote ; Humans ; Male ; Medical research ; Medicine ; Medicine & Public Health ; Medicine, Experimental ; Mutation ; Nucleotide sequencing ; Original Article ; Pedigree ; Phenotype ; Tachycardia, Ventricular - genetics ; Vascular Surgery ; Ventricular tachycardia ; Whole Genome Sequencing</subject><ispartof>Pediatric cardiology, 2020-12, Vol.41 (8), p.1783-1794</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2020</rights><rights>COPYRIGHT 2020 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-6700a9f1fb89718f6a4050f64e5b27fa154b8a948bcf226f30a6c73e111428673</citedby><cites>FETCH-LOGICAL-c414t-6700a9f1fb89718f6a4050f64e5b27fa154b8a948bcf226f30a6c73e111428673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00246-020-02446-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00246-020-02446-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32939586$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Du, Zhanhui</creatorcontrib><creatorcontrib>Kuang, Shan</creatorcontrib><creatorcontrib>Li, Yong</creatorcontrib><creatorcontrib>Han, Peng</creatorcontrib><creatorcontrib>Liu, Junnian</creatorcontrib><creatorcontrib>Wang, Zhiwei</creatorcontrib><creatorcontrib>Huang, Yingping</creatorcontrib><creatorcontrib>Guan, Yuanning</creatorcontrib><creatorcontrib>Xu, Xun</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Banerjee, Santasree</creatorcontrib><creatorcontrib>Pan, Silin</creatorcontrib><title>Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia</title><title>Pediatric cardiology</title><addtitle>Pediatr Cardiol</addtitle><addtitle>Pediatr Cardiol</addtitle><description>Idiopathic ventricular tachycardia (IVT) is the major cause of sudden cardiac death. Patients with IVT were usually manifested without structural heart disease. In this present study, we performed family-based whole genome sequencing (WGS) and Sanger sequencing for a 5-year-old Chinese boy with IVT and all the unaffected family members in order to identify the candidate gene and disease-causing mutation underlying the disease phenotype. Results showed that a novel heterozygous single-nucleotide duplication (c.128dup) and a novel heterozygous missense (c.3328A > G) variant in ABCA5 gene were identified in the proband. The single-nucleotide duplication (c.128dupT), inherited from his father and patrilineal grandfather, leads to a frameshift which results into the formation of a truncated ABCA5 protein of 50 (p.Leu43Phefs*8) amino acids. Hence, it is a loss-of-function mutation. The missense (c.3328A > G) variant, inherited from his mother, leads to the replacement of isoleucine by valine at the position of 1110 (p.Ile1110Val) of the ABCA5 protein. Multiple sequence alignment showed that p.Ile1110 is evolutionarily conserved among several species indicating both the structural and functional significance of the p.Ile1110 residue in the wild-type ABCA5 protein. Quantitative RT-PCR showed that the ABCA5 mRNA expression levels were decreased in the proband. These two novel variants of ABCA5 gene were co-segregated well among all the members of this family. Our present study also strongly supports the importance of using family-based whole genome sequencing for identifying novel candidate genes associated with IVT.</description><subject>Asian Continental Ancestry Group - genetics</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>Cardiac Surgery</subject><subject>Cardiology</subject><subject>Child, Preschool</subject><subject>Death, Sudden, Cardiac - epidemiology</subject><subject>DNA sequencing</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Medicine, Experimental</subject><subject>Mutation</subject><subject>Nucleotide sequencing</subject><subject>Original Article</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Tachycardia, Ventricular - genetics</subject><subject>Vascular Surgery</subject><subject>Ventricular tachycardia</subject><subject>Whole Genome Sequencing</subject><issn>0172-0643</issn><issn>1432-1971</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EokvhBTggS1y4pNiOnTjH7YqWShUgUcrRmjjjXVeJs9gJaI-8Od6mICEhZFkej79_5JmfkJecnXHG6reJMSGrggmWt8yRfERWXJai4E3NH5MV47UoWCXLE_IspTvGmGZaPSUnpWjKRulqRX5ewOD7Q3EOCTv6dTf2SC8xjAPSz_htxmB92NKrDsPknc_Ih_E79vQWoocwJeoDXZ9v1uoowuMN6CeYfMbpDz_tstKPe5h23tLbnIzezj1EegN2d7AQOw_PyRMHfcIXD-cp-XLx7mbzvrj-eHm1WV8XVnI5FVXNGDSOu1bn5rSrQDLFXCVRtaJ2wJVsNTRSt9YJUbmSQWXrEjnnUuiqLk_Jm6XuPo65sTSZwSeLfQ8BxzmZPMFSa9UontHXC7qFHo0Pbpwi2CNu1jVXimt-X_DsH1ReHQ7ejgGdz_m_BGIR2DimFNGZffQDxIPhzBwdNYujJjtq7h01MotePXx7bgfs_kh-W5iBcgFSfgpbjOZunGPIo_xf2V-Jm6l_</recordid><startdate>20201201</startdate><enddate>20201201</enddate><creator>Du, Zhanhui</creator><creator>Kuang, Shan</creator><creator>Li, Yong</creator><creator>Han, Peng</creator><creator>Liu, Junnian</creator><creator>Wang, Zhiwei</creator><creator>Huang, Yingping</creator><creator>Guan, Yuanning</creator><creator>Xu, Xun</creator><creator>Liu, Xin</creator><creator>Banerjee, Santasree</creator><creator>Pan, Silin</creator><general>Springer US</general><general>Springer</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></search><sort><creationdate>20201201</creationdate><title>Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia</title><author>Du, Zhanhui ; Kuang, Shan ; Li, Yong ; Han, Peng ; Liu, Junnian ; Wang, Zhiwei ; Huang, Yingping ; Guan, Yuanning ; Xu, Xun ; Liu, Xin ; Banerjee, Santasree ; Pan, Silin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c414t-6700a9f1fb89718f6a4050f64e5b27fa154b8a948bcf226f30a6c73e111428673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Asian Continental Ancestry Group - genetics</topic><topic>ATP-Binding Cassette Transporters - genetics</topic><topic>Cardiac Surgery</topic><topic>Cardiology</topic><topic>Child, Preschool</topic><topic>Death, Sudden, Cardiac - epidemiology</topic><topic>DNA sequencing</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Heart</topic><topic>Heart diseases</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Male</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Medicine, Experimental</topic><topic>Mutation</topic><topic>Nucleotide sequencing</topic><topic>Original Article</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Tachycardia, Ventricular - genetics</topic><topic>Vascular Surgery</topic><topic>Ventricular tachycardia</topic><topic>Whole Genome Sequencing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Du, Zhanhui</creatorcontrib><creatorcontrib>Kuang, Shan</creatorcontrib><creatorcontrib>Li, Yong</creatorcontrib><creatorcontrib>Han, Peng</creatorcontrib><creatorcontrib>Liu, Junnian</creatorcontrib><creatorcontrib>Wang, Zhiwei</creatorcontrib><creatorcontrib>Huang, Yingping</creatorcontrib><creatorcontrib>Guan, Yuanning</creatorcontrib><creatorcontrib>Xu, Xun</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Banerjee, Santasree</creatorcontrib><creatorcontrib>Pan, Silin</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>Pediatric cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Du, Zhanhui</au><au>Kuang, Shan</au><au>Li, Yong</au><au>Han, Peng</au><au>Liu, Junnian</au><au>Wang, Zhiwei</au><au>Huang, Yingping</au><au>Guan, Yuanning</au><au>Xu, Xun</au><au>Liu, Xin</au><au>Banerjee, Santasree</au><au>Pan, Silin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia</atitle><jtitle>Pediatric cardiology</jtitle><stitle>Pediatr Cardiol</stitle><addtitle>Pediatr Cardiol</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>41</volume><issue>8</issue><spage>1783</spage><epage>1794</epage><pages>1783-1794</pages><issn>0172-0643</issn><eissn>1432-1971</eissn><abstract>Idiopathic ventricular tachycardia (IVT) is the major cause of sudden cardiac death. Patients with IVT were usually manifested without structural heart disease. In this present study, we performed family-based whole genome sequencing (WGS) and Sanger sequencing for a 5-year-old Chinese boy with IVT and all the unaffected family members in order to identify the candidate gene and disease-causing mutation underlying the disease phenotype. Results showed that a novel heterozygous single-nucleotide duplication (c.128dup) and a novel heterozygous missense (c.3328A > G) variant in ABCA5 gene were identified in the proband. The single-nucleotide duplication (c.128dupT), inherited from his father and patrilineal grandfather, leads to a frameshift which results into the formation of a truncated ABCA5 protein of 50 (p.Leu43Phefs*8) amino acids. Hence, it is a loss-of-function mutation. The missense (c.3328A > G) variant, inherited from his mother, leads to the replacement of isoleucine by valine at the position of 1110 (p.Ile1110Val) of the ABCA5 protein. Multiple sequence alignment showed that p.Ile1110 is evolutionarily conserved among several species indicating both the structural and functional significance of the p.Ile1110 residue in the wild-type ABCA5 protein. Quantitative RT-PCR showed that the ABCA5 mRNA expression levels were decreased in the proband. These two novel variants of ABCA5 gene were co-segregated well among all the members of this family. Our present study also strongly supports the importance of using family-based whole genome sequencing for identifying novel candidate genes associated with IVT.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>32939586</pmid><doi>10.1007/s00246-020-02446-4</doi><tpages>12</tpages></addata></record> |
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subjects | Asian Continental Ancestry Group - genetics ATP-Binding Cassette Transporters - genetics Cardiac Surgery Cardiology Child, Preschool Death, Sudden, Cardiac - epidemiology DNA sequencing Genes Genetic aspects Genomes Genomics Heart Heart diseases Heterozygote Humans Male Medical research Medicine Medicine & Public Health Medicine, Experimental Mutation Nucleotide sequencing Original Article Pedigree Phenotype Tachycardia, Ventricular - genetics Vascular Surgery Ventricular tachycardia Whole Genome Sequencing |
title | Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia |
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