Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?
CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease. We...
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| Veröffentlicht in: | Genetics in medicine 2023-02, Vol.25 (2), p.100327-100327, Article 100327 |
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| creator | Barbier, Mathieu Davoine, Claire-Sophie Petit, Emilien Porché, Maximilien Guillot-Noel, Léna Sayah, Sabrina Fauret, Anne-Laure Neau, Jean-Philippe Guyant-Maréchal, Lucie Deffond, Didier Tranchant, Christine Goizet, Cyril Coarelli, Giulia Castrioto, Anna Klebe, Stephan Ewenczyk, Claire Heinzmann, Anna Charles, Perrine Tchikviladzé, Maya Van Broeckhoven, Christine Brice, Alexis Durr, Alexandra |
| description | CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease.
We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47).
STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode.
We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48. |
| doi_str_mv | 10.1016/j.gim.2022.10.009 |
| format | Article |
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We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47).
STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode.
We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.</description><identifier>ISSN: 1098-3600</identifier><identifier>EISSN: 1530-0366</identifier><identifier>DOI: 10.1016/j.gim.2022.10.009</identifier><identifier>PMID: 36422518</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alleles ; Cerebellar Ataxia - genetics ; Humans ; Phenotype ; SCA17 ; SCA48 ; Spinocerebellar Ataxias - genetics ; Spinocerebellar Ataxias - pathology ; STUB1, Spinocerebellar ataxia ; TBP ; Trinucleotide Repeat Expansion - genetics ; Ubiquitin-Protein Ligases - genetics</subject><ispartof>Genetics in medicine, 2023-02, Vol.25 (2), p.100327-100327, Article 100327</ispartof><rights>2022 American College of Medical Genetics and Genomics</rights><rights>Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-7bb4cc0f5ae9a06ea620c88768da8a05144973a62e4588e167c3d2c37c66f9733</citedby><cites>FETCH-LOGICAL-c396t-7bb4cc0f5ae9a06ea620c88768da8a05144973a62e4588e167c3d2c37c66f9733</cites><orcidid>0000-0002-5154-2163 ; 0000-0002-8921-7104</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36422518$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barbier, Mathieu</creatorcontrib><creatorcontrib>Davoine, Claire-Sophie</creatorcontrib><creatorcontrib>Petit, Emilien</creatorcontrib><creatorcontrib>Porché, Maximilien</creatorcontrib><creatorcontrib>Guillot-Noel, Léna</creatorcontrib><creatorcontrib>Sayah, Sabrina</creatorcontrib><creatorcontrib>Fauret, Anne-Laure</creatorcontrib><creatorcontrib>Neau, Jean-Philippe</creatorcontrib><creatorcontrib>Guyant-Maréchal, Lucie</creatorcontrib><creatorcontrib>Deffond, Didier</creatorcontrib><creatorcontrib>Tranchant, Christine</creatorcontrib><creatorcontrib>Goizet, Cyril</creatorcontrib><creatorcontrib>Coarelli, Giulia</creatorcontrib><creatorcontrib>Castrioto, Anna</creatorcontrib><creatorcontrib>Klebe, Stephan</creatorcontrib><creatorcontrib>Ewenczyk, Claire</creatorcontrib><creatorcontrib>Heinzmann, Anna</creatorcontrib><creatorcontrib>Charles, Perrine</creatorcontrib><creatorcontrib>Tchikviladzé, Maya</creatorcontrib><creatorcontrib>Van Broeckhoven, Christine</creatorcontrib><creatorcontrib>Brice, Alexis</creatorcontrib><creatorcontrib>Durr, Alexandra</creatorcontrib><title>Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?</title><title>Genetics in medicine</title><addtitle>Genet Med</addtitle><description>CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease.
We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47).
STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode.
We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.</description><subject>Alleles</subject><subject>Cerebellar Ataxia - genetics</subject><subject>Humans</subject><subject>Phenotype</subject><subject>SCA17</subject><subject>SCA48</subject><subject>Spinocerebellar Ataxias - genetics</subject><subject>Spinocerebellar Ataxias - pathology</subject><subject>STUB1, Spinocerebellar ataxia</subject><subject>TBP</subject><subject>Trinucleotide Repeat Expansion - genetics</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><issn>1098-3600</issn><issn>1530-0366</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1P3DAQhq0KxFf5Ab0gH7lkGduJncABFVQ-JKRW6nK2vM4EvNrYwfZW8O_r1QJHTvP1zquZh5AfDGYMmDxbzp7cOOPAealnAN03csAaARUIKXdKDl1bCQmwTw5TWgIwJTjskX0ha84b1h6Qt3ufMY7YO5ORRpzQZIqvk_HJBZ9oGOj86g81vqd_549X7JzeosfsLB1D7waHkYZIp3VE2rsn9GXg_DNGl423WHKaJueDxYgLXK1MpCabV2fS5XeyO5hVwuP3eEQeb37Nr--qh9-399c_HyorOpkrtVjU1sLQGOwMSDSSg21bJdvetAYaVtedEqWLddO2yKSyoudWKCvlUCbiiJxufacYXtaYsh5dsptbPIZ10lyJTtUgFS9StpXaGFKKOOgputHEN81Ab4jrpS7E9Yb4plWIl52Td_v1omD83PhAXAQXWwGWJ_8VYDpZhwVO7yLarPvgvrD_Dyc6kYo</recordid><startdate>202302</startdate><enddate>202302</enddate><creator>Barbier, Mathieu</creator><creator>Davoine, Claire-Sophie</creator><creator>Petit, Emilien</creator><creator>Porché, Maximilien</creator><creator>Guillot-Noel, Léna</creator><creator>Sayah, Sabrina</creator><creator>Fauret, Anne-Laure</creator><creator>Neau, Jean-Philippe</creator><creator>Guyant-Maréchal, Lucie</creator><creator>Deffond, Didier</creator><creator>Tranchant, Christine</creator><creator>Goizet, Cyril</creator><creator>Coarelli, Giulia</creator><creator>Castrioto, Anna</creator><creator>Klebe, Stephan</creator><creator>Ewenczyk, Claire</creator><creator>Heinzmann, Anna</creator><creator>Charles, Perrine</creator><creator>Tchikviladzé, Maya</creator><creator>Van Broeckhoven, Christine</creator><creator>Brice, Alexis</creator><creator>Durr, Alexandra</creator><general>Elsevier Inc</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/0000-0002-5154-2163</orcidid><orcidid>https://orcid.org/0000-0002-8921-7104</orcidid></search><sort><creationdate>202302</creationdate><title>Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?</title><author>Barbier, Mathieu ; Davoine, Claire-Sophie ; Petit, Emilien ; Porché, Maximilien ; Guillot-Noel, Léna ; Sayah, Sabrina ; Fauret, Anne-Laure ; Neau, Jean-Philippe ; Guyant-Maréchal, Lucie ; Deffond, Didier ; Tranchant, Christine ; Goizet, Cyril ; Coarelli, Giulia ; Castrioto, Anna ; Klebe, Stephan ; Ewenczyk, Claire ; Heinzmann, Anna ; Charles, Perrine ; Tchikviladzé, Maya ; Van Broeckhoven, Christine ; Brice, Alexis ; Durr, Alexandra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-7bb4cc0f5ae9a06ea620c88768da8a05144973a62e4588e167c3d2c37c66f9733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Alleles</topic><topic>Cerebellar Ataxia - genetics</topic><topic>Humans</topic><topic>Phenotype</topic><topic>SCA17</topic><topic>SCA48</topic><topic>Spinocerebellar Ataxias - genetics</topic><topic>Spinocerebellar Ataxias - pathology</topic><topic>STUB1, Spinocerebellar ataxia</topic><topic>TBP</topic><topic>Trinucleotide Repeat Expansion - genetics</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barbier, Mathieu</creatorcontrib><creatorcontrib>Davoine, Claire-Sophie</creatorcontrib><creatorcontrib>Petit, Emilien</creatorcontrib><creatorcontrib>Porché, Maximilien</creatorcontrib><creatorcontrib>Guillot-Noel, Léna</creatorcontrib><creatorcontrib>Sayah, Sabrina</creatorcontrib><creatorcontrib>Fauret, Anne-Laure</creatorcontrib><creatorcontrib>Neau, Jean-Philippe</creatorcontrib><creatorcontrib>Guyant-Maréchal, Lucie</creatorcontrib><creatorcontrib>Deffond, Didier</creatorcontrib><creatorcontrib>Tranchant, Christine</creatorcontrib><creatorcontrib>Goizet, Cyril</creatorcontrib><creatorcontrib>Coarelli, Giulia</creatorcontrib><creatorcontrib>Castrioto, Anna</creatorcontrib><creatorcontrib>Klebe, Stephan</creatorcontrib><creatorcontrib>Ewenczyk, Claire</creatorcontrib><creatorcontrib>Heinzmann, Anna</creatorcontrib><creatorcontrib>Charles, Perrine</creatorcontrib><creatorcontrib>Tchikviladzé, Maya</creatorcontrib><creatorcontrib>Van Broeckhoven, Christine</creatorcontrib><creatorcontrib>Brice, Alexis</creatorcontrib><creatorcontrib>Durr, Alexandra</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>Genetics in medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barbier, Mathieu</au><au>Davoine, Claire-Sophie</au><au>Petit, Emilien</au><au>Porché, Maximilien</au><au>Guillot-Noel, Léna</au><au>Sayah, Sabrina</au><au>Fauret, Anne-Laure</au><au>Neau, Jean-Philippe</au><au>Guyant-Maréchal, Lucie</au><au>Deffond, Didier</au><au>Tranchant, Christine</au><au>Goizet, Cyril</au><au>Coarelli, Giulia</au><au>Castrioto, Anna</au><au>Klebe, Stephan</au><au>Ewenczyk, Claire</au><au>Heinzmann, Anna</au><au>Charles, Perrine</au><au>Tchikviladzé, Maya</au><au>Van Broeckhoven, Christine</au><au>Brice, Alexis</au><au>Durr, Alexandra</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?</atitle><jtitle>Genetics in medicine</jtitle><addtitle>Genet Med</addtitle><date>2023-02</date><risdate>2023</risdate><volume>25</volume><issue>2</issue><spage>100327</spage><epage>100327</epage><pages>100327-100327</pages><artnum>100327</artnum><issn>1098-3600</issn><eissn>1530-0366</eissn><abstract>CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease.
We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47).
STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode.
We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36422518</pmid><doi>10.1016/j.gim.2022.10.009</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-5154-2163</orcidid><orcidid>https://orcid.org/0000-0002-8921-7104</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alleles Cerebellar Ataxia - genetics Humans Phenotype SCA17 SCA48 Spinocerebellar Ataxias - genetics Spinocerebellar Ataxias - pathology STUB1, Spinocerebellar ataxia TBP Trinucleotide Repeat Expansion - genetics Ubiquitin-Protein Ligases - genetics |
| title | Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias? |
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