Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.
Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.
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DOI：
10.1002/mgg3.1647
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发表时间：
2021-04
影响因子：
2
通讯作者：
Surti U
中科院分区：
文献类型：
--
作者：
Liao J;Coffman KA;Locker J;Padiath QS;Nmezi B;Filipink RA;Hu J;Sathanoori M;Madan-Khetarpal S;McGuire M;Schreiber A;Moran R;Friedman N;Hoffner L;Rajkovic A;Yatsenko SA;Surti U
良性遗传性舞蹈病（BHC）是一种常染色体显性遗传疾病，其特征是早发性非进行性不自主运动。尽管NKX2-1突变或缺失是BHC的原因，但一些BHC家族的NKX2-1基因没有致病性改变，表明NKX2-1非编码调控元件的突变也可能发挥作用。通过使用全基因组微阵列分析，我们在三个明显不相关的 BHC 家族中发现了 117 Kb 的起始缺失，这些家族对于 NKX2-1 序列变异呈阴性。靶向下一代测序分析证实了该缺失，并表明它是复杂的局部基因组重排的一部分。此外，我们还在一个孤立的 BHC 病例中检测到了 648 Kb 的从头删除。这两个缺失均位于染色体 14q13.2-q13.3 上 NKX2-1 的下游，并与之前报道的 6 个病例共享一个 33 Kb 的最小重叠区域。该区域没有基因，但包含多个进化上高度保守的非编码序列。我们认为，该关键区域中 NKX2-1 表达所需的潜在调控元件的缺失导致了这些患者的 BHC 表型，这是 BHC 的一种新的致病机制。我们报告了一系列良性遗传性舞蹈病患者，其 14q13 邻近 NKX2-1 缺失。进一步的遗传分析表明，在这些缺失共享的重叠区域中存在潜在的非编码调控元件。
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. We report a series of benign hereditary chorea patients with 14q13 deletions proximal to NKX2‐1. Further genetic analysis suggests the presence of potential non‐coding regulatory elements in the overlapping region shared by these deletions.
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影响因子：
9.5
作者：
Thorvaldsdóttir H;Robinson JT;Mesirov JP
通讯作者：
Mesirov JP
影响因子：
1.9
作者：
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DOI：
10.1093/database/bax028
发表时间：
2017-01-01
期刊：
Database : the journal of biological databases and curation
影响因子：
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作者：
Fishilevich S;Nudel R;Rappaport N;Hadar R;Plaschkes I;Iny Stein T;Rosen N;Kohn A;Twik M;Safran M;Lancet D;Cohen D
通讯作者：
Cohen D
影响因子：
9.9
作者：
Breedveld, GJ;Percy, AK;Arts, WFM
通讯作者：
Arts, WFM
DOI：
10.1111/j.1469-8749.2012.04287.x
发表时间：
2012-07-01
影响因子：
3.8
作者：
Dale, Russell C.;Grattan-Smith, Padraic;Peters, Greg B.
通讯作者：
Peters, Greg B.