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

Autor: Magrinelli F; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom., Rocca C; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.; William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom., Simone R; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Zenezini Chiozzi R; Mass-Spectrometry, Science Technology Platforms, University College London, London, United Kingdom., Jaunmuktane Z; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom., Mencacci NE; Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA., Tinazzi M; Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy., Jayawant S; Paediatric Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom., Nemeth AH; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.; Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom., Demidov G; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Houlden H; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Bhatia KP; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Jazyk: angličtina
Zdroj: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2023 Feb; Vol. 38 (2), pp. 347-353. Date of Electronic Publication: 2022 Nov 23.
DOI: 10.1002/mds.29280
Abstrakt: 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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
(© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Databáze: MEDLINE
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