采用全外显子组测序来鉴定与遗传性心脏传导疾病相关的一种新的LMNA基因突变。
Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease.
作者信息
Lai Chun-Chi, Yeh Yung-Hsin, Hsieh Wen-Ping, Kuo Chi-Tai, Wang Wen-Ching, Chu Chia-Han, Hung Chiu-Lien, Cheng Chia-Yang, Tsai Hsin-Yi, Lee Jia-Lin, Tang Chuan-Yi, Hsu Lung-An
机构信息
Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan.
First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan.
出版信息
PLoS One. 2013 Dec 12;8(12):e83322. doi: 10.1371/journal.pone.0083322. eCollection 2013.
BACKGROUND
Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases.
OBJECTIVE
To investigate the genetic background of a family affected by inherited CCD.
METHODS AND RESULTS
We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model.
CONCLUSIONS
Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases.
背景
遗传性心脏传导疾病（CCD）较为罕见，但由众多基因的突变引起。最近，全外显子组测序已成功鉴定出罕见单基因孟德尔疾病的致病突变。
目的
研究一个受遗传性CCD影响的家系的遗传背景。
方法与结果
我们使用全外显子组测序研究了一个有多名家庭成员受CCD影响的中国家系。利用系谱信息，我们提出在核纤层蛋白A/C（LMNA）基因中的一个杂合错义突变（c.G695T，Gly232Val）作为该家系中CCD易感性的候选突变。该突变是新发现的，根据结构模型预测，预计会影响LMNA卷曲螺旋杆状结构域的构象。通过在细胞模型中表达该突变，进一步验证了其在核纤层不稳定中的致病性。
结论
我们的结果表明，全外显子组测序是鉴定遗传性传导疾病潜在候选基因的一种可行方法。
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