Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease
Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes. We performed whole exome sequencing...
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| Veröffentlicht in: | Neurology 2013-03, Vol.80 (11), p.982-989 |
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| creator | NUYTEMANS, Karen BADEMCI, Guney SCOTT, William K VANCE, Jeffery M INCHAUSTI, Vanessa DRESSEN, Amy KINNAMON, Daniel D MEHTA, Arpit LIYONG WANG ZÜCHNER, Stephan BEECHAM, Gary W MARTIN, Eden R |
| description | Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.
We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with |
| doi_str_mv | 10.1212/WNL.0b013e31828727d4 |
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We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.
We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.
We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.</description><identifier>ISSN: 0028-3878</identifier><identifier>EISSN: 1526-632X</identifier><identifier>DOI: 10.1212/WNL.0b013e31828727d4</identifier><identifier>PMID: 23408866</identifier><identifier>CODEN: NEURAI</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Biological and medical sciences ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Eukaryotic Initiation Factor-4G - genetics ; Exome - genetics ; Female ; Genetic Variation - genetics ; Humans ; Male ; Medical sciences ; Middle Aged ; Neurology ; Parkinson Disease - diagnosis ; Parkinson Disease - genetics ; Sequence Analysis, DNA - methods ; Vesicular Transport Proteins - genetics</subject><ispartof>Neurology, 2013-03, Vol.80 (11), p.982-989</ispartof><rights>2014 INIST-CNRS</rights><rights>2013 American Academy of Neurology 2013 American Academy of Neurology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-475f8669cc674d53475bf7d2bd77b8adce8e5fe75f62589fb4f69bd82771b09b3</citedby><cites>FETCH-LOGICAL-c438t-475f8669cc674d53475bf7d2bd77b8adce8e5fe75f62589fb4f69bd82771b09b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27157290$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23408866$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>NUYTEMANS, Karen</creatorcontrib><creatorcontrib>BADEMCI, Guney</creatorcontrib><creatorcontrib>SCOTT, William K</creatorcontrib><creatorcontrib>VANCE, Jeffery M</creatorcontrib><creatorcontrib>INCHAUSTI, Vanessa</creatorcontrib><creatorcontrib>DRESSEN, Amy</creatorcontrib><creatorcontrib>KINNAMON, Daniel D</creatorcontrib><creatorcontrib>MEHTA, Arpit</creatorcontrib><creatorcontrib>LIYONG WANG</creatorcontrib><creatorcontrib>ZÜCHNER, Stephan</creatorcontrib><creatorcontrib>BEECHAM, Gary W</creatorcontrib><creatorcontrib>MARTIN, Eden R</creatorcontrib><title>Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease</title><title>Neurology</title><addtitle>Neurology</addtitle><description>Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.
We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.
We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.
We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biological and medical sciences</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Eukaryotic Initiation Factor-4G - genetics</subject><subject>Exome - genetics</subject><subject>Female</subject><subject>Genetic Variation - genetics</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Neurology</subject><subject>Parkinson Disease - diagnosis</subject><subject>Parkinson Disease - genetics</subject><subject>Sequence Analysis, DNA - methods</subject><subject>Vesicular Transport Proteins - genetics</subject><issn>0028-3878</issn><issn>1526-632X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkdtKJDEQhoO46Hh4A5HcCHvTbg7dSfpGkMETDOuAx7uQdFc0bk-iyYzsvr0RR129KlL11V-V-hHaoWSfMsp-3fye7BNLKAdOFVOSyb5eQSPaMFEJzm5X0YgQpiqupFpHGzk_EFKKsl1D64zXRCkhRmh6cx8HwPA3zgBneFpA6Hy4w9HhZBLgZ5O8CfOMfcBHZ8f1CcUm9Ph6esGb19zUpD8-5Bhw7zOYDFvohzNDhu1l3ERXx0eX49Nqcn5yNj6cVF3N1byqZePKAm3XCVn3DS9v62TPbC-lVabvQEHjoFCCNap1tnaitb1iUlJLWss30cGb7uPCzqDwYZ7MoB-Tn5n0T0fj9ddK8Pf6Lj5rLhrOiCgCP5cCKZZv57me-dzBMJgAcZE15VRwKbliBa3f0C7FnBO4jzGU6FczdDFDfzejtO3-v-JH0_v1C7C3BEzuzOCSKcfPn5ykjWQt4S8Np5Mj</recordid><startdate>20130312</startdate><enddate>20130312</enddate><creator>NUYTEMANS, Karen</creator><creator>BADEMCI, Guney</creator><creator>SCOTT, William K</creator><creator>VANCE, Jeffery M</creator><creator>INCHAUSTI, Vanessa</creator><creator>DRESSEN, Amy</creator><creator>KINNAMON, Daniel D</creator><creator>MEHTA, Arpit</creator><creator>LIYONG WANG</creator><creator>ZÜCHNER, Stephan</creator><creator>BEECHAM, Gary W</creator><creator>MARTIN, Eden R</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><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>5PM</scope></search><sort><creationdate>20130312</creationdate><title>Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease</title><author>NUYTEMANS, Karen ; BADEMCI, Guney ; SCOTT, William K ; VANCE, Jeffery M ; INCHAUSTI, Vanessa ; DRESSEN, Amy ; KINNAMON, Daniel D ; MEHTA, Arpit ; LIYONG WANG ; ZÜCHNER, Stephan ; BEECHAM, Gary W ; MARTIN, Eden R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-475f8669cc674d53475bf7d2bd77b8adce8e5fe75f62589fb4f69bd82771b09b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biological and medical sciences</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Eukaryotic Initiation Factor-4G - genetics</topic><topic>Exome - genetics</topic><topic>Female</topic><topic>Genetic Variation - genetics</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Neurology</topic><topic>Parkinson Disease - diagnosis</topic><topic>Parkinson Disease - genetics</topic><topic>Sequence Analysis, DNA - methods</topic><topic>Vesicular Transport Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>NUYTEMANS, Karen</creatorcontrib><creatorcontrib>BADEMCI, Guney</creatorcontrib><creatorcontrib>SCOTT, William K</creatorcontrib><creatorcontrib>VANCE, Jeffery M</creatorcontrib><creatorcontrib>INCHAUSTI, Vanessa</creatorcontrib><creatorcontrib>DRESSEN, Amy</creatorcontrib><creatorcontrib>KINNAMON, Daniel D</creatorcontrib><creatorcontrib>MEHTA, Arpit</creatorcontrib><creatorcontrib>LIYONG WANG</creatorcontrib><creatorcontrib>ZÜCHNER, Stephan</creatorcontrib><creatorcontrib>BEECHAM, Gary W</creatorcontrib><creatorcontrib>MARTIN, Eden R</creatorcontrib><collection>Pascal-Francis</collection><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>PubMed Central (Full Participant titles)</collection><jtitle>Neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>NUYTEMANS, Karen</au><au>BADEMCI, Guney</au><au>SCOTT, William K</au><au>VANCE, Jeffery M</au><au>INCHAUSTI, Vanessa</au><au>DRESSEN, Amy</au><au>KINNAMON, Daniel D</au><au>MEHTA, Arpit</au><au>LIYONG WANG</au><au>ZÜCHNER, Stephan</au><au>BEECHAM, Gary W</au><au>MARTIN, Eden R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease</atitle><jtitle>Neurology</jtitle><addtitle>Neurology</addtitle><date>2013-03-12</date><risdate>2013</risdate><volume>80</volume><issue>11</issue><spage>982</spage><epage>989</epage><pages>982-989</pages><issn>0028-3878</issn><eissn>1526-632X</eissn><coden>NEURAI</coden><abstract>Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.
We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.
We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.
We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>23408866</pmid><doi>10.1212/WNL.0b013e31828727d4</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Neurology, 2013-03, Vol.80 (11), p.982-989 |
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| subjects | Adult Aged Aged, 80 and over Biological and medical sciences Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Eukaryotic Initiation Factor-4G - genetics Exome - genetics Female Genetic Variation - genetics Humans Male Medical sciences Middle Aged Neurology Parkinson Disease - diagnosis Parkinson Disease - genetics Sequence Analysis, DNA - methods Vesicular Transport Proteins - genetics |
| title | Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease |
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