Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.


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
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

e1647

Subventions

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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Auteurs

Jun Liao (J)

Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Keith A Coffman (KA)

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Joseph Locker (J)

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Quasar S Padiath (QS)

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Bruce Nmezi (B)

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Robyn A Filipink (RA)

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Jie Hu (J)

Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Malini Sathanoori (M)

Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Suneeta Madan-Khetarpal (S)

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Marianne McGuire (M)

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Allison Schreiber (A)

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

Rocio Moran (R)

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

Neil Friedman (N)

Center for Pediatric Neurology, Cleveland Clinic, Cleveland, OH, USA.

Lori Hoffner (L)

Magee Womens Research Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Aleksandar Rajkovic (A)

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Magee Womens Research Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Svetlana A Yatsenko (SA)

Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Magee Womens Research Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Urvashi Surti (U)

Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Magee Womens Research Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

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