A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis
Creators: name: De Boer, Elke
name: Ockeloen, Charlotte W.
name: Matalonga, Leslie
name: Horvath, Rita
name: Rodenburg, Richard J.
name: Coenen, Marieke J. H.
name: Janssen, Mirian
name: Henssen, Dylan
name: Paramonov, Ida
name: Trimouille, Aurélien
name: Kleefstra, Tjitske
name: Vissers, Lisenka E. L. M.
name: Cohen, Enzo
name: Cuesta, Isabel
name: Danis, Daniel
name: Denommé-Pichon, Anne-Sophie
name: Duffourd, Yannis
name: Gilissen, Christian
name: Johari, Mridul
name: Laurie, Steven
name: Li, Shuang
name: Nelson, Isabelle
name: Peters, Sophia
name: Prasanth, Sivakumar
name: Robinson, Peter
name: Sablauskas, Karolis
name: Savarese, Marco
name: Steyaert, Wouter
name: Töpf, Ana
name: Van Der Velde, Joeri K.
name: Vitobello, Antonio
name: Banka, Siddharth
name: Benetti, Elisa
name: Casari, Giorgio
name: Ciolfi, Andrea
name: Clayton-Smith, Jill
name: Dallapiccola, Bruno
name: Faivre, Laurence
name: Haack, Tobias B.
name: Hammarsjö, Anna
name: Havlovicova, Marketa
name: Hoischen, Alexander
name: Hugon, Anne
name: Jackson, Adam
name: Lindstrand, Anna
name: López-Martín, Estrella
name: Macek, Milan
name: Nigro, Vicenzo
name: Nordgren, Ann
name: Pettersson, Maria
name: Pinelli, Michele
name: Pizzi, Simone
name: Posada, Manuel
name: Radio, Francesca Clementina
name: Renieri, Alessandra
name: Rooryck, Caroline
name: Ryba, Lukas
name: Schwarz, Martin
name: Tartaglia, Marco
name: Thauvin, Christel
name: Torella, Annalaura
name: Verloes, Alain
name: Vissers, Lisenka
name: Vyshka, Klea
name: Zurek, Birte
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Brief Communication
/692/308/2056
/692/699/375
/692/699/375/366
/692/308/575
/45/23
brief-communication

description: Funder: The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257
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 &gt; C; NC_012920.1:n.62T &gt; 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 &gt; 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.