Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.
NKX2-1
benign hereditary chorea
chromosome 14q13.2-q13.3
copy number variations
non-coding regulatory elements
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
18
02
2021
received:
05
10
2020
accepted:
19
02
2021
pubmed:
6
3
2021
medline:
15
12
2021
entrez:
5
3
2021
Statut:
ppublish
Résumé
Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early-onset non-progressive involuntary movements. Although NKX2-1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2-1 gene, indicating that mutations of non-coding regulatory elements of NKX2-1 may also play a role. By using whole-genome microarray analysis, we identified a 117 Kb founder deletion in three apparently unrelated BHC families that were negative for NKX2-1 sequence variants. Targeted next generation sequencing analysis confirmed the deletion and showed that it was part of a complex local genomic rearrangement. In addition, we also detected a 648 Kb de novo deletion in an isolated BHC case. Both deletions are located downstream from NKX2-1 on chromosome 14q13.2-q13.3 and share a 33 Kb smallest region of overlap with six previously reported cases. This region has no gene but contains multiple evolutionarily highly conserved non-coding sequences. We propose that the deletion of potential regulatory elements necessary for NKX2-1 expression in this critical region is responsible for BHC phenotype in these patients, and this is a novel disease-causing mechanism for BHC.
Sections du résumé
BACKGROUND
Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early-onset non-progressive involuntary movements. Although NKX2-1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2-1 gene, indicating that mutations of non-coding regulatory elements of NKX2-1 may also play a role.
METHODS AND RESULTS
By using whole-genome microarray analysis, we identified a 117 Kb founder deletion in three apparently unrelated BHC families that were negative for NKX2-1 sequence variants. Targeted next generation sequencing analysis confirmed the deletion and showed that it was part of a complex local genomic rearrangement. In addition, we also detected a 648 Kb de novo deletion in an isolated BHC case. Both deletions are located downstream from NKX2-1 on chromosome 14q13.2-q13.3 and share a 33 Kb smallest region of overlap with six previously reported cases. This region has no gene but contains multiple evolutionarily highly conserved non-coding sequences.
CONCLUSION
We propose that the deletion of potential regulatory elements necessary for NKX2-1 expression in this critical region is responsible for BHC phenotype in these patients, and this is a novel disease-causing mechanism for BHC.
Identifiants
pubmed: 33666368
doi: 10.1002/mgg3.1647
pmc: PMC8123744
doi:
Substances chimiques
NKX2-1 protein, human
0
Thyroid Nuclear Factor 1
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1647Subventions
Organisme : NINDS NIH HHS
ID : R21 NS106087
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS104384
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG046897
Pays : United States
Organisme : NINDS NIH HHS
ID : R33 NS104384
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS086749
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095884
Pays : United States
Informations de copyright
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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