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Case Reports
. 2021 Apr;9(4):e1647.
doi: 10.1002/mgg3.1647. Epub 2021 Mar 5.

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

Jun Liao  1   2 , Keith A Coffman  3 , Joseph Locker  4 , Quasar S Padiath  2 , Bruce Nmezi  2 , Robyn A Filipink  3 , Jie Hu  1   5 , Malini Sathanoori  1   4   5 , Suneeta Madan-Khetarpal  3 , Marianne McGuire  3 , Allison Schreiber  6 , Rocio Moran  6 , Neil Friedman  7 , Lori Hoffner  8 , Aleksandar Rajkovic  2   4   5   8 , Svetlana A Yatsenko  1   2   4   5   8 , Urvashi Surti  1   2   4   5   8
Affiliations
Case Reports

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

Jun Liao et al. Mol Genet Genomic Med. 2021 Apr.

Abstract

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.

Keywords: NKX2-1; benign hereditary chorea; chromosome 14q13.2-q13.3; copy number variations; non-coding regulatory elements.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Pedigrees of three BHC families reported in this paper. Affected individuals are represented by closed symbols and unaffected individuals by open symbols. Probands are indicated by arrows. Genotypes of all tested individuals are listed below their symbols. +/+, normal microarray result; del/+, a heterozygous 14q13.3 deletion was detected
FIGURE 2
FIGURE 2
(a) Schematic illustration of chromosome 14q13.2‐q13.3 region showing deletions in three BHC families and an isolated case in this study, six deletions reported in previous studies, and PhyloP scores from 100 Vertebrates Basewise Conservation Analysis in the minimum overlapping region. (b) Metaphase FISH results for probands of Families 1 and 2 by using BAC probes RP11‐363G18 (red) and RP11‐74F2 (red) respectively. BAC probe RP11‐265I9 (green) is used as a control. Normal signals are indicated by arrows and diminished ones are indicated by arrowheads
FIGURE 3
FIGURE 3
Next generation sequence analysis of the genomic region encompassing 14q13 deletions
See this image and copyright information in PMC

References

    1. Barnett, C. P. , Mencel, J. J. , Gecz, J. , Waters, W. , Kirwin, S. M. , Vinette, K. M. B. , Uppill, M. , & Nicholl, J. (2012). Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2‐1. American Journal of Medical Genetics Part A, 158A(12), 3168–3173. 10.1002/ajmg.a.35456 - DOI - PubMed
    1. Bauer, P. , Kreuz, F. R. , Burk, K. , Saft, C. , Andrich, J. , Heilemann, H. , Riess, O. , & Schols, L. (2006). Mutations in TITF1 are not relevant to sporadic and familial chorea of unknown cause. Movement Disorders, 21(10), 1734–1737. 10.1002/mds.21031 - DOI - PubMed
    1. Breedveld, G. J. , Percy, A. K. , MacDonald, M. E. , de Vries, B. B. , Yapijakis, C. , Dure, L. S. , Ippel, E. F. , Sandkuijl, L. A., Heutink, P. , & Arts, W. F. (2002). Clinical and genetic heterogeneity in benign hereditary chorea. Neurology, 59(4), 579–584. 10.1212/WNL.59.4.579 - DOI - PubMed
    1. Breedveld, G. J. , van Dongen, J. W. , Danesino, C. , Guala, A. , Percy, A. K. , Dure, L. S. , Harper, P. , Arts, W. F. , Lazarou, L. P. , Van Der Linde, H. , de Vries, B. , Joosse, M. , & Heutink, P. (2002). Mutations in TITF‐1 are associated with benign hereditary chorea. Human Molecular Genetics, 11(8), 971–979. 10.1093/hmg/11.8.971 - DOI - PubMed
    1. Dale, R. C. , Grattan‐Smith, P. , Nicholson, M. , & Peters, G. B. (2012). Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single‐centre study. Developmental Medicine & Child Neurology, 54(7), 618–623. 10.1111/j.1469-8749.2012.04287.x - DOI - PubMed

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