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Tytuł:
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Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.
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Autorzy:
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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.
Coffman KA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Locker J; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Padiath QS; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Nmezi B; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Filipink RA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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.
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.
Madan-Khetarpal S; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
McGuire M; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Schreiber A; Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
Moran R; Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
Friedman N; Center for Pediatric Neurology, Cleveland Clinic, Cleveland, OH, USA.
Hoffner L; Magee Womens Research Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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.
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.
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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Źródło:
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Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2021 Apr; Vol. 9 (4), pp. e1647. Date of Electronic Publication: 2021 Mar 05.
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Typ publikacji:
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Case Reports; Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: [Hoboken, NJ] : John Wiley & Sons, [2013]-
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MeSH Terms:
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Regulatory Sequences, Nucleic Acid*
Chorea/*genetics
Thyroid Nuclear Factor 1/*genetics
Adolescent ; Child ; Chorea/pathology ; Chromosomes, Human, Pair 14/genetics ; Conserved Sequence ; Female ; Humans ; Male ; Pedigree ; Sequence Deletion
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Grant Information:
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R21 NS106087 United States NS NINDS NIH HHS; R21 NS104384 United States NS NINDS NIH HHS; R21 AG046897 United States AG NIA NIH HHS; R33 NS104384 United States NS NINDS NIH HHS; T32 NS086749 United States NS NINDS NIH HHS; R01 NS095884 United States NS NINDS NIH HHS
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Contributed Indexing:
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Keywords: NKX2-1; benign hereditary chorea; chromosome 14q13.2-q13.3; copy number variations; non-coding regulatory elements
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Substance Nomenclature:
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0 (NKX2-1 protein, human)
0 (Thyroid Nuclear Factor 1)
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Entry Date(s):
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Date Created: 20210305 Date Completed: 20211210 Latest Revision: 20230513
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Update Code:
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20240104
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PubMed Central ID:
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PMC8123744
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DOI:
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10.1002/mgg3.1647
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PMID:
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33666368
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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.
(© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
