Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions
Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Bra...
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| Veröffentlicht in: | Clinical genetics 2016-08, Vol.90 (2), p.134-140 |
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| creator | Souza, G.N. Kersting, N. Krum-Santos, A.C. Santos, A.S.P. Furtado, G.V. Pacheco, D. Gonçalves, T.A. Saute, J.A. Schuler-Faccini, L. Mattos, E.P. Saraiva-Pereira, M.L. Jardim, L.B. |
| description | Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta‐CAGexp from parent–offspring pairs, and delta‐CAGexp between siblings were obtained. One hundred and fifty‐nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta‐CAGexp among 115 direct parent–offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta‐CAGexp between 269 siblings correlated with their delta‐of‐age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception. |
| doi_str_mv | 10.1111/cge.12719 |
| format | Article |
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Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta‐CAGexp from parent–offspring pairs, and delta‐CAGexp between siblings were obtained. One hundred and fifty‐nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta‐CAGexp among 115 direct parent–offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta‐CAGexp between 269 siblings correlated with their delta‐of‐age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.</description><identifier>ISSN: 0009-9163</identifier><identifier>EISSN: 1399-0004</identifier><identifier>DOI: 10.1111/cge.12719</identifier><identifier>PMID: 26693702</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adolescent ; Adult ; Age Factors ; Age of Onset ; Alleles ; Asymptomatic Diseases ; Ataxia ; Ataxin-3 - genetics ; CAG expansion instabilities ; CAG expansion transmission ; Cell division ; Chromosome Segregation ; Female ; Gene Frequency ; Genetic disorders ; Genomic Instability ; Heterozygote ; Humans ; Inheritance Patterns ; Machado-Joseph disease ; Machado-Joseph Disease - genetics ; Machado-Joseph Disease - pathology ; Male ; Meiosis ; minimal prevalence ; MJD ; Pedigree ; Population genetics ; Repressor Proteins - genetics ; SCA3 ; segregation distortion ; Severity of Illness Index ; Sex Factors ; Siblings ; spinocerebellar ataxia type 3 ; Trinucleotide Repeat Expansion</subject><ispartof>Clinical genetics, 2016-08, Vol.90 (2), p.134-140</ispartof><rights>2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><rights>2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><rights>2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4949-3ef8071e837da32c60da84bec61b0da7164b93667924548ac3a1c8e258d66afd3</citedby><cites>FETCH-LOGICAL-c4949-3ef8071e837da32c60da84bec61b0da7164b93667924548ac3a1c8e258d66afd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcge.12719$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcge.12719$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26693702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Souza, G.N.</creatorcontrib><creatorcontrib>Kersting, N.</creatorcontrib><creatorcontrib>Krum-Santos, A.C.</creatorcontrib><creatorcontrib>Santos, A.S.P.</creatorcontrib><creatorcontrib>Furtado, G.V.</creatorcontrib><creatorcontrib>Pacheco, D.</creatorcontrib><creatorcontrib>Gonçalves, T.A.</creatorcontrib><creatorcontrib>Saute, J.A.</creatorcontrib><creatorcontrib>Schuler-Faccini, L.</creatorcontrib><creatorcontrib>Mattos, E.P.</creatorcontrib><creatorcontrib>Saraiva-Pereira, M.L.</creatorcontrib><creatorcontrib>Jardim, L.B.</creatorcontrib><title>Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions</title><title>Clinical genetics</title><addtitle>Clin Genet</addtitle><description>Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta‐CAGexp from parent–offspring pairs, and delta‐CAGexp between siblings were obtained. One hundred and fifty‐nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta‐CAGexp among 115 direct parent–offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta‐CAGexp between 269 siblings correlated with their delta‐of‐age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Age Factors</subject><subject>Age of Onset</subject><subject>Alleles</subject><subject>Asymptomatic Diseases</subject><subject>Ataxia</subject><subject>Ataxin-3 - genetics</subject><subject>CAG expansion instabilities</subject><subject>CAG expansion transmission</subject><subject>Cell division</subject><subject>Chromosome Segregation</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Genetic disorders</subject><subject>Genomic Instability</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Inheritance Patterns</subject><subject>Machado-Joseph disease</subject><subject>Machado-Joseph Disease - genetics</subject><subject>Machado-Joseph Disease - pathology</subject><subject>Male</subject><subject>Meiosis</subject><subject>minimal prevalence</subject><subject>MJD</subject><subject>Pedigree</subject><subject>Population genetics</subject><subject>Repressor Proteins - genetics</subject><subject>SCA3</subject><subject>segregation distortion</subject><subject>Severity of Illness Index</subject><subject>Sex Factors</subject><subject>Siblings</subject><subject>spinocerebellar ataxia type 3</subject><subject>Trinucleotide Repeat Expansion</subject><issn>0009-9163</issn><issn>1399-0004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNks9uEzEQh1cIRNPCgRdAlrjAYRt7vfEfblUoKSiFSoA4WrPe2dRl411sR03egYfGIW0PSEj4MmPpm08e_VwULxg9ZflM7QpPWSWZflRMGNe6pJTWj4tJLrrUTPCj4jjGm3zlcqafFkeVEJpLWk2KX19G5weLARvsewgEEmwdkLQbkfDpJdhraIfy4xBxvCatiwgR35KIq4ArSG7wZISUMPhIwLekA5uGEInzXb9Bb51f5T4maFzv0o4MHcHtmElsyfxsQVIAH9cuxmyKz4onHfQRn9_Vk-Lb-_Ov84ty-XnxYX62LG2ta11y7BSVDBWXLfDKCtqCqhu0gjW5lUzUjeZCSF3Vs1qB5cCswmqmWiGga_lJ8frgHcPwc4MxmfwCu9_f47CJhimqhFCqkv-D1kwrKWhGX_2F3gyb4PMie4rzqhZaZ-rNgbJhiDFgZ8bg1hB2hlGzT9PkNM2fNDP78s64adbYPpD38WVgegBuXY-7f5vMfHF-rywPEy4m3D5MQPhhhMy_w3z_tDBXS17xy6sL847_BpLIuS8</recordid><startdate>201608</startdate><enddate>201608</enddate><creator>Souza, G.N.</creator><creator>Kersting, N.</creator><creator>Krum-Santos, A.C.</creator><creator>Santos, A.S.P.</creator><creator>Furtado, G.V.</creator><creator>Pacheco, D.</creator><creator>Gonçalves, T.A.</creator><creator>Saute, J.A.</creator><creator>Schuler-Faccini, L.</creator><creator>Mattos, E.P.</creator><creator>Saraiva-Pereira, M.L.</creator><creator>Jardim, L.B.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</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>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201608</creationdate><title>Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions</title><author>Souza, G.N. ; Kersting, N. ; Krum-Santos, A.C. ; Santos, A.S.P. ; Furtado, G.V. ; Pacheco, D. ; Gonçalves, T.A. ; Saute, J.A. ; Schuler-Faccini, L. ; Mattos, E.P. ; Saraiva-Pereira, M.L. ; Jardim, L.B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4949-3ef8071e837da32c60da84bec61b0da7164b93667924548ac3a1c8e258d66afd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Age Factors</topic><topic>Age of Onset</topic><topic>Alleles</topic><topic>Asymptomatic Diseases</topic><topic>Ataxia</topic><topic>Ataxin-3 - genetics</topic><topic>CAG expansion instabilities</topic><topic>CAG expansion transmission</topic><topic>Cell division</topic><topic>Chromosome Segregation</topic><topic>Female</topic><topic>Gene Frequency</topic><topic>Genetic disorders</topic><topic>Genomic Instability</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Inheritance Patterns</topic><topic>Machado-Joseph disease</topic><topic>Machado-Joseph Disease - genetics</topic><topic>Machado-Joseph Disease - pathology</topic><topic>Male</topic><topic>Meiosis</topic><topic>minimal prevalence</topic><topic>MJD</topic><topic>Pedigree</topic><topic>Population genetics</topic><topic>Repressor Proteins - genetics</topic><topic>SCA3</topic><topic>segregation distortion</topic><topic>Severity of Illness Index</topic><topic>Sex Factors</topic><topic>Siblings</topic><topic>spinocerebellar ataxia type 3</topic><topic>Trinucleotide Repeat Expansion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Souza, G.N.</creatorcontrib><creatorcontrib>Kersting, N.</creatorcontrib><creatorcontrib>Krum-Santos, A.C.</creatorcontrib><creatorcontrib>Santos, A.S.P.</creatorcontrib><creatorcontrib>Furtado, G.V.</creatorcontrib><creatorcontrib>Pacheco, D.</creatorcontrib><creatorcontrib>Gonçalves, T.A.</creatorcontrib><creatorcontrib>Saute, J.A.</creatorcontrib><creatorcontrib>Schuler-Faccini, L.</creatorcontrib><creatorcontrib>Mattos, E.P.</creatorcontrib><creatorcontrib>Saraiva-Pereira, M.L.</creatorcontrib><creatorcontrib>Jardim, L.B.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Souza, G.N.</au><au>Kersting, N.</au><au>Krum-Santos, A.C.</au><au>Santos, A.S.P.</au><au>Furtado, G.V.</au><au>Pacheco, D.</au><au>Gonçalves, T.A.</au><au>Saute, J.A.</au><au>Schuler-Faccini, L.</au><au>Mattos, E.P.</au><au>Saraiva-Pereira, M.L.</au><au>Jardim, L.B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions</atitle><jtitle>Clinical genetics</jtitle><addtitle>Clin Genet</addtitle><date>2016-08</date><risdate>2016</risdate><volume>90</volume><issue>2</issue><spage>134</spage><epage>140</epage><pages>134-140</pages><issn>0009-9163</issn><eissn>1399-0004</eissn><abstract>Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta‐CAGexp from parent–offspring pairs, and delta‐CAGexp between siblings were obtained. One hundred and fifty‐nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta‐CAGexp among 115 direct parent–offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta‐CAGexp between 269 siblings correlated with their delta‐of‐age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>26693702</pmid><doi>10.1111/cge.12719</doi><tpages>7</tpages></addata></record> |
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| source | Wiley Online Library - AutoHoldings Journals; MEDLINE |
| subjects | Adolescent Adult Age Factors Age of Onset Alleles Asymptomatic Diseases Ataxia Ataxin-3 - genetics CAG expansion instabilities CAG expansion transmission Cell division Chromosome Segregation Female Gene Frequency Genetic disorders Genomic Instability Heterozygote Humans Inheritance Patterns Machado-Joseph disease Machado-Joseph Disease - genetics Machado-Joseph Disease - pathology Male Meiosis minimal prevalence MJD Pedigree Population genetics Repressor Proteins - genetics SCA3 segregation distortion Severity of Illness Index Sex Factors Siblings spinocerebellar ataxia type 3 Trinucleotide Repeat Expansion |
| title | Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions |
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