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

Francesca Magrinelli*, Clarissa Rocca, Roberto Simone, Riccardo Zenezini Chiozzi, Zane Jaunmuktane, Niccolò E. Mencacci, Michele Tinazzi, Sandeep Jayawant, Andrea H. Nemeth, German Demidov, Henry Houlden, Kailash P. Bhatia

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)347-353
Number of pages7
JournalMovement Disorders
Issue number2
StatePublished - Feb 2023


  • brain-lung-thyroid syndrome
  • chorea
  • dystonia
  • mobile element insertion
  • thyroid transcription factor-1

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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