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A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

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dc.contributor.author de Boer, Elke
dc.contributor.author Ockeloen, Charlotte W.
dc.contributor.author Matalonga, Leslie
dc.contributor.author Horvath, Rita
dc.contributor.author Solve-RD SNV-indel working group
dc.contributor.author Rodenburg, Richard J.
dc.contributor.author Coenen, Marieke J.H.
dc.contributor.author Janssen, Mirian
dc.contributor.author Henssen, Dylan
dc.contributor.author Gilissen, Christian
dc.contributor.author Steyaert, Wouter
dc.contributor.author Paramonov, Ida
dc.contributor.author Solve-RD-DITF-ITHACA
dc.contributor.author Trimouille, Aurélien
dc.contributor.author Kleefstra, Tjitske
dc.contributor.author Verloes, Alain
dc.contributor.author Vissers, Lisenka E.L.M.
dc.date.accessioned 2021-11-18T06:41:27Z
dc.date.available 2021-11-18T06:41:27Z
dc.date.issued 2021
dc.identifier.citation de Boer E, Ockeloen CW, Matalonga L, Horvath R; Solve-RD SNV-indel working group, Rodenburg RJ, Coenen MJH, Janssen M, Henssen D, Gilissen C, Steyaert W, Paramonov I; Solve-RD-DITF-ITHACA, Trimouille A, Kleefstra T, Verloes A, Vissers LELM. A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet. 2021;29(9):1359-68. DOI: 10.1038/s41431-021-00900-2
dc.identifier.issn 1018-4813
dc.identifier.uri http://hdl.handle.net/10230/49010
dc.description.abstract The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Eur J Hum Genet. 2021;29(9):1359-68
dc.rights © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41431-021-00900-2
dc.subject.keyword Genetics research
dc.subject.keyword Neurodevelopmental disorders
dc.subject.keyword Neurological disorders
dc.subject.keyword Translational research
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/779257
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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