In:
Movement Disorders, Wiley, Vol. 38, No. 2 ( 2023-02), p. 347-353
Abstract:
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 Alu Ya5 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_557ins Alu 541_556dup) segregated with the disease phenotype. Conclusions We identified a de novo exonic Alu Ya5 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.
Type of Medium:
Online Resource
ISSN:
0885-3185
,
1531-8257
Language:
English
Publisher:
Wiley
Publication Date:
2023
detail.hit.zdb_id:
2041249-6
