@article{e6f0ff79787f47b58a7f594ed5f7ded3,
title = "Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder",
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.",
keywords = "brain-lung-thyroid syndrome, chorea, dystonia, mobile element insertion, thyroid transcription factor-1",
author = "Francesca Magrinelli and Clarissa Rocca and Roberto Simone and {Zenezini Chiozzi}, Riccardo and Zane Jaunmuktane and Mencacci, {Niccol{\`o} E.} and Michele Tinazzi and Sandeep Jayawant and Nemeth, {Andrea H.} and German Demidov and Henry Houlden and Bhatia, {Kailash P.}",
note = "Funding Information: We are most grateful to the family discussed here for participating in this study. We would like to acknowledge the entire staff of Solve-RD as well as the entire staff of the Human Protein Atlas project and GTEx project. We thank Dr. David Pellerin (Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, United Kingdom) for his kind review of the final manuscript. Funding Information: This project received funding from the European Union's Horizon 2020 research and innovation program under grant agreement number 779257 (Solve‐RD). Funding agency: Funding Information: F.M. was supported by the Edmond J. Safra Foundation. C.R., R.S., and R.Z.C. have no disclosures. Z.J. was supported by the Department of Health's NIHR Biomedical Research Centre's funding scheme to UCLH. N.E.M. was supported by a Parkinson's Foundation grant and by the Global Parkinson's Genetics Program (GP2). M.T. and S.J. have no disclosures. A.H.N. was funded by Ataxia UK, Action Medical Research, the John Fell Fund, and Alzheimer's Research UK. G.D. received funding from the European Union's Horizon 2020 research and innovation program under grant agreement number 779257 (Solve‐RD). H.H. was funded by MRC (MR/S01165X/1, MR/S005021/1, G0601943), Department of Health's NIHR Biomedical Research Centre's funding scheme to UCLH, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and the European Union's Horizon 2020 research and innovation program under grant agreement number 779257 (Solve‐RD). K.P.B. has received grant support from Wellcome/MRC, NIHR, Parkinson's UK, and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook (Oxford University Press, 2008), (Oxford University Press, 2012), and (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, and Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals, and the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society. Parkinson's Disease and Other Movement Disorders Marsden's Book of Movement Disorders Case Studies in Movement Disorders: Common and Uncommon Presentations Publisher Copyright: {\textcopyright} 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",
year = "2023",
month = feb,
doi = "10.1002/mds.29280",
language = "English (US)",
volume = "38",
pages = "347--353",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley and Sons Inc.",
number = "2",
}