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Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder |
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| Authors: | Francesca Magrinelli MD PhD Clarissa Rocca MSc Roberto Simone PhD Riccardo Zenezini Chiozzi PhD Zane Jaunmuktane MD FRCPath Niccolò E. Mencacci MD PhD Michele Tinazzi MD PhD Sandeep Jayawant MD Andrea H. Nemeth MD PhD German Demidov PhD Henry Houlden MD PhD Kailash P. Bhatia MD DM FRCP |
| Affiliation: | 1. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom;2. 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;3. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom;4. Mass-Spectrometry, Science Technology Platforms, University College London, London, United Kingdom;5. Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA;6. Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy;7. Paediatric Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom;8. 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;9. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany |
| Abstract: | BackgroundHeterozygous 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.ObjectiveTo 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.MethodsThe 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.ResultsA 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.ConclusionsWe 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. |
| Keywords: | brain-lung-thyroid syndrome chorea dystonia mobile element insertion thyroid transcription factor-1 |