Large‐Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes
Background Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, someti...
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| Veröffentlicht in: | Movement disorders 2024-03, Vol.39 (3), p.526-538 |
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| creator | Thomsen, Mirja Marth, Katrin Loens, Sebastian Everding, Judith Junker, Johanna Borngräber, Friederike Ott, Fabian Jesús, Silvia Gelderblom, Mathias Odorfer, Thorsten Kuhlenbäumer, Gregor Kim, Han‐Joon Schaeffer, Eva Becktepe, Jos Kasten, Meike Brüggemann, Norbert Pfister, Robert Kollewe, Katja Krauss, Joachim K. Lohmann, Ebba Hinrichs, Frauke Berg, Daniela Jeon, Beomseok Busch, Hauke Altenmüller, Eckart Mir, Pablo Kamm, Christoph Volkmann, Jens Zittel, Simone Ferbert, Andreas Zeuner, Kirsten E. Rolfs, Arndt Bauer, Peter Kühn, Andrea A. Bäumer, Tobias Klein, Christine Lohmann, Katja |
| description | Background
Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co‐occurring movement disorders such as Parkinson's disease (PD).
Objectives
To screen >2000 patients with dystonia or PD for rare variants in known dystonia‐causing genes.
Methods
We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next‐generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature.
Results
We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency |
| doi_str_mv | 10.1002/mds.29693 |
| format | Article |
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Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co‐occurring movement disorders such as Parkinson's disease (PD).
Objectives
To screen >2000 patients with dystonia or PD for rare variants in known dystonia‐causing genes.
Methods
We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next‐generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature.
Results
We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic.
Conclusion
This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT‐KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</description><identifier>ISSN: 0885-3185</identifier><identifier>EISSN: 1531-8257</identifier><identifier>DOI: 10.1002/mds.29693</identifier><identifier>PMID: 38214203</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>DNA methylation ; Dystonia ; GCH1 ; Gene frequency ; Genes ; GNAL ; KMT2B ; monogenic ; Movement disorders ; Neurodegenerative diseases ; Parkinson's disease ; primary dystonia ; PRKRA ; SGCE ; THAP1 ; TOR1A</subject><ispartof>Movement disorders, 2024-03, Vol.39 (3), p.526-538</ispartof><rights>2024 The Authors. published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</rights><rights>2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</rights><rights>2024. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3483-c331a56ee2ae51ee754cfdc67ec6f772a99abfbf66416ca2b304dfdc0bfff0b73</cites><orcidid>0000-0002-0675-9064 ; 0000-0003-2491-3544 ; 0000-0001-8219-9663 ; 0000-0002-0792-4383 ; 0000-0002-5121-1460 ; 0000-0002-7618-2336 ; 0000-0001-8695-7919 ; 0000-0001-9650-6820 ; 0000-0003-1656-302X ; 0000-0002-3767-6376 ; 0000-0001-5969-6899</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmds.29693$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmds.29693$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38214203$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thomsen, Mirja</creatorcontrib><creatorcontrib>Marth, Katrin</creatorcontrib><creatorcontrib>Loens, Sebastian</creatorcontrib><creatorcontrib>Everding, Judith</creatorcontrib><creatorcontrib>Junker, Johanna</creatorcontrib><creatorcontrib>Borngräber, Friederike</creatorcontrib><creatorcontrib>Ott, Fabian</creatorcontrib><creatorcontrib>Jesús, Silvia</creatorcontrib><creatorcontrib>Gelderblom, Mathias</creatorcontrib><creatorcontrib>Odorfer, Thorsten</creatorcontrib><creatorcontrib>Kuhlenbäumer, Gregor</creatorcontrib><creatorcontrib>Kim, Han‐Joon</creatorcontrib><creatorcontrib>Schaeffer, Eva</creatorcontrib><creatorcontrib>Becktepe, Jos</creatorcontrib><creatorcontrib>Kasten, Meike</creatorcontrib><creatorcontrib>Brüggemann, Norbert</creatorcontrib><creatorcontrib>Pfister, Robert</creatorcontrib><creatorcontrib>Kollewe, Katja</creatorcontrib><creatorcontrib>Krauss, Joachim K.</creatorcontrib><creatorcontrib>Lohmann, Ebba</creatorcontrib><creatorcontrib>Hinrichs, Frauke</creatorcontrib><creatorcontrib>Berg, Daniela</creatorcontrib><creatorcontrib>Jeon, Beomseok</creatorcontrib><creatorcontrib>Busch, Hauke</creatorcontrib><creatorcontrib>Altenmüller, Eckart</creatorcontrib><creatorcontrib>Mir, Pablo</creatorcontrib><creatorcontrib>Kamm, Christoph</creatorcontrib><creatorcontrib>Volkmann, Jens</creatorcontrib><creatorcontrib>Zittel, Simone</creatorcontrib><creatorcontrib>Ferbert, Andreas</creatorcontrib><creatorcontrib>Zeuner, Kirsten E.</creatorcontrib><creatorcontrib>Rolfs, Arndt</creatorcontrib><creatorcontrib>Bauer, Peter</creatorcontrib><creatorcontrib>Kühn, Andrea A.</creatorcontrib><creatorcontrib>Bäumer, Tobias</creatorcontrib><creatorcontrib>Klein, Christine</creatorcontrib><creatorcontrib>Lohmann, Katja</creatorcontrib><title>Large‐Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes</title><title>Movement disorders</title><addtitle>Mov Disord</addtitle><description>Background
Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co‐occurring movement disorders such as Parkinson's disease (PD).
Objectives
To screen >2000 patients with dystonia or PD for rare variants in known dystonia‐causing genes.
Methods
We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next‐generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature.
Results
We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic.
Conclusion
This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT‐KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</description><subject>DNA methylation</subject><subject>Dystonia</subject><subject>GCH1</subject><subject>Gene frequency</subject><subject>Genes</subject><subject>GNAL</subject><subject>KMT2B</subject><subject>monogenic</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>Parkinson's disease</subject><subject>primary dystonia</subject><subject>PRKRA</subject><subject>SGCE</subject><subject>THAP1</subject><subject>TOR1A</subject><issn>0885-3185</issn><issn>1531-8257</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp10MtKxDAUBuAgio6jC19ACm50MWMubZq6k_EKIwqj65KmJxppkzFpkdn5CD6jT2KcUReCmxwCHz_n_AjtETwmGNPjtg5jWvCCraEByRgZCZrl62iAhchGjIhsC22H8IwxIRnhm2iLCUpSitkAqan0j_Dx9j5TsoFkpjyANfbxJLl7Auu6xdyoRNo6uek72RlnZZPM5qA637eJscl1cI3soF6aiWsrY-PnbBE6Z41MLsFC2EEbWjYBdr_nED1cnN9PrkbT28vryel0pFgqWHwZkRkHoBIyApBnqdK14jkorvOcyqKQla405ynhStKK4bSOAFdaa1zlbIgOV7lz7156CF3ZmqCgaaQF14eSFrTAjGBRRHrwhz673sfjvlTOhOA0rjRERyulvAvBgy7n3rTSL0qCy6_my9h8uWw-2v3vxL5qof6VP1VHcLwCr6aBxf9J5c3ZbBX5CelOjuw</recordid><startdate>202403</startdate><enddate>202403</enddate><creator>Thomsen, Mirja</creator><creator>Marth, Katrin</creator><creator>Loens, Sebastian</creator><creator>Everding, Judith</creator><creator>Junker, Johanna</creator><creator>Borngräber, Friederike</creator><creator>Ott, Fabian</creator><creator>Jesús, Silvia</creator><creator>Gelderblom, Mathias</creator><creator>Odorfer, Thorsten</creator><creator>Kuhlenbäumer, Gregor</creator><creator>Kim, Han‐Joon</creator><creator>Schaeffer, Eva</creator><creator>Becktepe, Jos</creator><creator>Kasten, Meike</creator><creator>Brüggemann, Norbert</creator><creator>Pfister, Robert</creator><creator>Kollewe, Katja</creator><creator>Krauss, Joachim K.</creator><creator>Lohmann, Ebba</creator><creator>Hinrichs, Frauke</creator><creator>Berg, Daniela</creator><creator>Jeon, Beomseok</creator><creator>Busch, Hauke</creator><creator>Altenmüller, Eckart</creator><creator>Mir, Pablo</creator><creator>Kamm, Christoph</creator><creator>Volkmann, Jens</creator><creator>Zittel, Simone</creator><creator>Ferbert, Andreas</creator><creator>Zeuner, Kirsten E.</creator><creator>Rolfs, Arndt</creator><creator>Bauer, Peter</creator><creator>Kühn, Andrea A.</creator><creator>Bäumer, Tobias</creator><creator>Klein, Christine</creator><creator>Lohmann, Katja</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, 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Dystonia Genes</title><author>Thomsen, Mirja ; Marth, Katrin ; Loens, Sebastian ; Everding, Judith ; Junker, Johanna ; Borngräber, Friederike ; Ott, Fabian ; Jesús, Silvia ; Gelderblom, Mathias ; Odorfer, Thorsten ; Kuhlenbäumer, Gregor ; Kim, Han‐Joon ; Schaeffer, Eva ; Becktepe, Jos ; Kasten, Meike ; Brüggemann, Norbert ; Pfister, Robert ; Kollewe, Katja ; Krauss, Joachim K. ; Lohmann, Ebba ; Hinrichs, Frauke ; Berg, Daniela ; Jeon, Beomseok ; Busch, Hauke ; Altenmüller, Eckart ; Mir, Pablo ; Kamm, Christoph ; Volkmann, Jens ; Zittel, Simone ; Ferbert, Andreas ; Zeuner, Kirsten E. ; Rolfs, Arndt ; Bauer, Peter ; Kühn, Andrea A. ; Bäumer, Tobias ; Klein, Christine ; Lohmann, Katja</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3483-c331a56ee2ae51ee754cfdc67ec6f772a99abfbf66416ca2b304dfdc0bfff0b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>DNA methylation</topic><topic>Dystonia</topic><topic>GCH1</topic><topic>Gene frequency</topic><topic>Genes</topic><topic>GNAL</topic><topic>KMT2B</topic><topic>monogenic</topic><topic>Movement disorders</topic><topic>Neurodegenerative diseases</topic><topic>Parkinson's disease</topic><topic>primary dystonia</topic><topic>PRKRA</topic><topic>SGCE</topic><topic>THAP1</topic><topic>TOR1A</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thomsen, Mirja</creatorcontrib><creatorcontrib>Marth, Katrin</creatorcontrib><creatorcontrib>Loens, Sebastian</creatorcontrib><creatorcontrib>Everding, Judith</creatorcontrib><creatorcontrib>Junker, Johanna</creatorcontrib><creatorcontrib>Borngräber, Friederike</creatorcontrib><creatorcontrib>Ott, Fabian</creatorcontrib><creatorcontrib>Jesús, Silvia</creatorcontrib><creatorcontrib>Gelderblom, Mathias</creatorcontrib><creatorcontrib>Odorfer, Thorsten</creatorcontrib><creatorcontrib>Kuhlenbäumer, 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Arndt</creatorcontrib><creatorcontrib>Bauer, Peter</creatorcontrib><creatorcontrib>Kühn, Andrea A.</creatorcontrib><creatorcontrib>Bäumer, Tobias</creatorcontrib><creatorcontrib>Klein, Christine</creatorcontrib><creatorcontrib>Lohmann, Katja</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Movement disorders</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thomsen, Mirja</au><au>Marth, Katrin</au><au>Loens, Sebastian</au><au>Everding, Judith</au><au>Junker, Johanna</au><au>Borngräber, Friederike</au><au>Ott, Fabian</au><au>Jesús, Silvia</au><au>Gelderblom, Mathias</au><au>Odorfer, Thorsten</au><au>Kuhlenbäumer, Gregor</au><au>Kim, Han‐Joon</au><au>Schaeffer, Eva</au><au>Becktepe, Jos</au><au>Kasten, Meike</au><au>Brüggemann, Norbert</au><au>Pfister, Robert</au><au>Kollewe, Katja</au><au>Krauss, Joachim K.</au><au>Lohmann, Ebba</au><au>Hinrichs, Frauke</au><au>Berg, Daniela</au><au>Jeon, Beomseok</au><au>Busch, Hauke</au><au>Altenmüller, Eckart</au><au>Mir, Pablo</au><au>Kamm, Christoph</au><au>Volkmann, Jens</au><au>Zittel, Simone</au><au>Ferbert, Andreas</au><au>Zeuner, Kirsten E.</au><au>Rolfs, Arndt</au><au>Bauer, Peter</au><au>Kühn, Andrea A.</au><au>Bäumer, Tobias</au><au>Klein, Christine</au><au>Lohmann, Katja</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Large‐Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes</atitle><jtitle>Movement disorders</jtitle><addtitle>Mov Disord</addtitle><date>2024-03</date><risdate>2024</risdate><volume>39</volume><issue>3</issue><spage>526</spage><epage>538</epage><pages>526-538</pages><issn>0885-3185</issn><eissn>1531-8257</eissn><abstract>Background
Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co‐occurring movement disorders such as Parkinson's disease (PD).
Objectives
To screen >2000 patients with dystonia or PD for rare variants in known dystonia‐causing genes.
Methods
We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next‐generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature.
Results
We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic.
Conclusion
This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT‐KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>38214203</pmid><doi>10.1002/mds.29693</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-0675-9064</orcidid><orcidid>https://orcid.org/0000-0003-2491-3544</orcidid><orcidid>https://orcid.org/0000-0001-8219-9663</orcidid><orcidid>https://orcid.org/0000-0002-0792-4383</orcidid><orcidid>https://orcid.org/0000-0002-5121-1460</orcidid><orcidid>https://orcid.org/0000-0002-7618-2336</orcidid><orcidid>https://orcid.org/0000-0001-8695-7919</orcidid><orcidid>https://orcid.org/0000-0001-9650-6820</orcidid><orcidid>https://orcid.org/0000-0003-1656-302X</orcidid><orcidid>https://orcid.org/0000-0002-3767-6376</orcidid><orcidid>https://orcid.org/0000-0001-5969-6899</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_proquest_miscellaneous_2929031089 |
| source | Wiley Online Library Journals Frontfile Complete |
| subjects | DNA methylation Dystonia GCH1 Gene frequency Genes GNAL KMT2B monogenic Movement disorders Neurodegenerative diseases Parkinson's disease primary dystonia PRKRA SGCE THAP1 TOR1A |
| title | Large‐Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes |
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