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Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder

Magrinelli, Francesca; Rocca, Clarissa; Simone, Roberto; Zenezini Chiozzi, Riccardo; Jaunmuktane, Zane; Mencacci, Niccolò E; Tinazzi, Michele; ... Bhatia, Kailash P; + view all (2022) Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder. Movement Disorders 10.1002/mds.29280. (In press). Green open access

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Abstract

BACKGROUND: Heterozygous NKX2-1 loss-of-function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood-onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease-causing structural variants whose detection in routine diagnostics remains challenging. OBJECTIVE: To establish the molecular diagnosis of two first-degree relatives with clinically suspected NKX2-1-related disorder who had negative NKX2-1 Sanger (SS), whole-exome (WES), and whole-genome (WGS) sequencing. METHODS: The proband's WES was analyzed for MEIs. A candidate MEI in NKX2-1 underwent optimized SS after plasmid cloning. Functional studies exploring NKX2-1 haploinsufficiency at RNA and protein levels were performed. RESULTS: A 347-bp AluYa5 insertion with a 65-bp poly-A tail followed by a 16-bp duplication of the pre-insertion wild-type sequence in exon 3 of NKX2-1 (ENST00000354822.7:c.556_557insAlu541_556dup) segregated with the disease phenotype. CONCLUSIONS: We identified a de novo exonic AluYa5 insertion causing NKX2-1-related disorder in SS/WES/WGS-negative cases, suggesting that MEI analysis of short-read sequencing data or targeted long-read sequencing could unmask the molecular diagnosis of unsolved MD cases.

Type: Article
Title: Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/mds.29280
Publisher version: https://doi.org/10.1002/mds.29280
Language: English
Additional information: Copyright © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: brain-lung-thyroid syndrome, chorea, dystonia, mobile element insertion, thyroid transcription factor-1
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10160855
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