Defining the epsilon-sarcoglycan (SGCE) gene phenotypic signature in myoclonus-dystonia: a reappraisal of genetic testing criteria.
Identifieur interne : 000A34 ( Main/Exploration ); précédent : 000A33; suivant : 000A35Defining the epsilon-sarcoglycan (SGCE) gene phenotypic signature in myoclonus-dystonia: a reappraisal of genetic testing criteria.
Auteurs : Miryam Carecchio [Royaume-Uni] ; Monia Magliozzi ; Massimiliano Copetti ; Alessandro Ferraris ; Laura Bernardini ; Monica Bonetti ; Giovanni Defazio ; Mark J. Edwards ; Isabella Torrente ; Fabio Pellegrini ; Cristoforo Comi ; Kailash P. Bhatia ; Enza Maria ValenteSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2013.
English descriptors
- KwdEn :
- Adult, Dystonic Disorders (diagnosis), Dystonic Disorders (genetics), Dystonic Disorders (physiopathology), Exons (genetics), Female, Genetic Association Studies, Genetic Predisposition to Disease (genetics), Humans, Male, Middle Aged, Mutation (genetics), Phenotype, ROC Curve, Reproducibility of Results, Sarcoglycans (genetics), Sensitivity and Specificity.
- MESH :
- chemical , genetics : Sarcoglycans.
- diagnosis : Dystonic Disorders.
- genetics : Dystonic Disorders, Exons, Genetic Predisposition to Disease, Mutation.
- physiopathology : Dystonic Disorders.
- Adult, Female, Genetic Association Studies, Humans, Male, Middle Aged, Phenotype, ROC Curve, Reproducibility of Results, Sensitivity and Specificity.
Abstract
Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes.
DOI: 10.1002/mds.25506
PubMed: 23677909
Affiliations:
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Edwards</name></author><author><name sortKey="Torrente, Isabella" sort="Torrente, Isabella" uniqKey="Torrente I" first="Isabella" last="Torrente">Isabella Torrente</name></author><author><name sortKey="Pellegrini, Fabio" sort="Pellegrini, Fabio" uniqKey="Pellegrini F" first="Fabio" last="Pellegrini">Fabio Pellegrini</name></author><author><name sortKey="Comi, Cristoforo" sort="Comi, Cristoforo" uniqKey="Comi C" first="Cristoforo" last="Comi">Cristoforo Comi</name></author><author><name sortKey="Bhatia, Kailash P" sort="Bhatia, Kailash P" uniqKey="Bhatia K" first="Kailash P" last="Bhatia">Kailash P. Bhatia</name></author><author><name sortKey="Valente, Enza Maria" sort="Valente, Enza Maria" uniqKey="Valente E" first="Enza Maria" last="Valente">Enza Maria Valente</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Dystonic Disorders (diagnosis)</term><term>Dystonic Disorders (genetics)</term><term>Dystonic Disorders (physiopathology)</term><term>Exons (genetics)</term><term>Female</term><term>Genetic Association Studies</term><term>Genetic Predisposition to Disease (genetics)</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Mutation (genetics)</term><term>Phenotype</term><term>ROC Curve</term><term>Reproducibility of Results</term><term>Sarcoglycans (genetics)</term><term>Sensitivity and Specificity</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Sarcoglycans</term></keywords><keywords scheme="MESH" qualifier="diagnosis" xml:lang="en"><term>Dystonic Disorders</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Dystonic Disorders</term><term>Exons</term><term>Genetic Predisposition to Disease</term><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Dystonic Disorders</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Female</term><term>Genetic Association Studies</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Phenotype</term><term>ROC Curve</term><term>Reproducibility of Results</term><term>Sensitivity and Specificity</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement></list><tree><noCountry><name sortKey="Bernardini, Laura" sort="Bernardini, Laura" uniqKey="Bernardini L" first="Laura" last="Bernardini">Laura Bernardini</name><name sortKey="Bhatia, Kailash P" sort="Bhatia, Kailash P" uniqKey="Bhatia K" first="Kailash P" last="Bhatia">Kailash P. Bhatia</name><name sortKey="Bonetti, Monica" sort="Bonetti, Monica" uniqKey="Bonetti M" first="Monica" last="Bonetti">Monica Bonetti</name><name sortKey="Comi, Cristoforo" sort="Comi, Cristoforo" uniqKey="Comi C" first="Cristoforo" last="Comi">Cristoforo Comi</name><name sortKey="Copetti, Massimiliano" sort="Copetti, Massimiliano" uniqKey="Copetti M" first="Massimiliano" last="Copetti">Massimiliano Copetti</name><name sortKey="Defazio, Giovanni" sort="Defazio, Giovanni" uniqKey="Defazio G" first="Giovanni" last="Defazio">Giovanni Defazio</name><name sortKey="Edwards, Mark J" sort="Edwards, Mark J" uniqKey="Edwards M" first="Mark J" last="Edwards">Mark J. Edwards</name><name sortKey="Ferraris, Alessandro" sort="Ferraris, Alessandro" uniqKey="Ferraris A" first="Alessandro" last="Ferraris">Alessandro Ferraris</name><name sortKey="Magliozzi, Monia" sort="Magliozzi, Monia" uniqKey="Magliozzi M" first="Monia" last="Magliozzi">Monia Magliozzi</name><name sortKey="Pellegrini, Fabio" sort="Pellegrini, Fabio" uniqKey="Pellegrini F" first="Fabio" last="Pellegrini">Fabio Pellegrini</name><name sortKey="Torrente, Isabella" sort="Torrente, Isabella" uniqKey="Torrente I" first="Isabella" last="Torrente">Isabella Torrente</name><name sortKey="Valente, Enza Maria" sort="Valente, Enza Maria" uniqKey="Valente E" first="Enza Maria" last="Valente">Enza Maria Valente</name></noCountry><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Carecchio, Miryam" sort="Carecchio, Miryam" uniqKey="Carecchio M" first="Miryam" last="Carecchio">Miryam Carecchio</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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