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A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing

BACKGROUND: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood‐onset progressive dystonia. METHODS: The splicing impact of c.5073C>T was assessed using an in vitro exon‐trapping ass...

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Autores principales: Grosz, Bianca R., Tisch, Stephen, Tchan, Michel C., Fung, Victor S. C., Darveniza, Paul, Fellner, Avi, Kurian, Manju A., McLean, Alison, Tomlinson, Susan E., Smyth, Renee, Devery, Sophie, Wu, Kathy H. C., Kennerson, Marina L., Kumar, Kishore R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034664/
https://www.ncbi.nlm.nih.gov/pubmed/35293157
http://dx.doi.org/10.1002/mgg3.1923
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author Grosz, Bianca R.
Tisch, Stephen
Tchan, Michel C.
Fung, Victor S. C.
Darveniza, Paul
Fellner, Avi
Kurian, Manju A.
McLean, Alison
Tomlinson, Susan E.
Smyth, Renee
Devery, Sophie
Wu, Kathy H. C.
Kennerson, Marina L.
Kumar, Kishore R.
author_facet Grosz, Bianca R.
Tisch, Stephen
Tchan, Michel C.
Fung, Victor S. C.
Darveniza, Paul
Fellner, Avi
Kurian, Manju A.
McLean, Alison
Tomlinson, Susan E.
Smyth, Renee
Devery, Sophie
Wu, Kathy H. C.
Kennerson, Marina L.
Kumar, Kishore R.
author_sort Grosz, Bianca R.
collection PubMed
description BACKGROUND: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood‐onset progressive dystonia. METHODS: The splicing impact of c.5073C>T was assessed using an in vitro exon‐trapping assay. The genomic region of KMT2B exons 23–26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C>T variant was then introduced through site‐directed mutagenesis. The KMT2B wild‐type and c.5073C>T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat Ins2 sequences. RESULTS: Sanger sequencing of the PCR products revealed that c.5073C>T caused a novel splice donor site and therefore a 5‐bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7). CONCLUSION: To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B‐related dystonia.
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spelling pubmed-90346642022-04-25 A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing Grosz, Bianca R. Tisch, Stephen Tchan, Michel C. Fung, Victor S. C. Darveniza, Paul Fellner, Avi Kurian, Manju A. McLean, Alison Tomlinson, Susan E. Smyth, Renee Devery, Sophie Wu, Kathy H. C. Kennerson, Marina L. Kumar, Kishore R. Mol Genet Genomic Med Clinical Reports BACKGROUND: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood‐onset progressive dystonia. METHODS: The splicing impact of c.5073C>T was assessed using an in vitro exon‐trapping assay. The genomic region of KMT2B exons 23–26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C>T variant was then introduced through site‐directed mutagenesis. The KMT2B wild‐type and c.5073C>T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat Ins2 sequences. RESULTS: Sanger sequencing of the PCR products revealed that c.5073C>T caused a novel splice donor site and therefore a 5‐bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7). CONCLUSION: To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B‐related dystonia. John Wiley and Sons Inc. 2022-03-16 /pmc/articles/PMC9034664/ /pubmed/35293157 http://dx.doi.org/10.1002/mgg3.1923 Text en © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Clinical Reports
Grosz, Bianca R.
Tisch, Stephen
Tchan, Michel C.
Fung, Victor S. C.
Darveniza, Paul
Fellner, Avi
Kurian, Manju A.
McLean, Alison
Tomlinson, Susan E.
Smyth, Renee
Devery, Sophie
Wu, Kathy H. C.
Kennerson, Marina L.
Kumar, Kishore R.
A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing
title A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing
title_full A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing
title_fullStr A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing
title_full_unstemmed A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing
title_short A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing
title_sort novel synonymous kmt2b variant in a patient with dystonia causes aberrant splicing
topic Clinical Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034664/
https://www.ncbi.nlm.nih.gov/pubmed/35293157
http://dx.doi.org/10.1002/mgg3.1923
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