DOI: 10.1002/mgg3.1647; PMCID: PMC8123744
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.
Mol Genet Genomic Med
NKX2-1; benign hereditary chorea; chromosome 14q13.2-q13.3; copy number variations; non-coding regulatory elements
Liao, J., Coffman, K. A., Locker, J., Padiath, Q. S., Nmezi, B., Filipink, R. A., Hu, J., Sathanoori, M., Madan-Khetarpal, S., McGuire, M., Schreiber, A., Moran, R., Friedman, N., Hoffner, L., Rajkovic, A., Yatsenko, S. A., Surti, U. Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea. Mol Genet Genomic Med 9, 1647-1647 (2021).