Marsman Roos F, Bardai Abdennasser, Postma Alex V, Res Jan C J, Koopmann Tamara T, Beekman Leander, van der Wal Allard C, Pinto Yigal M, Lekanne Deprez Ronald H, Wilde Arthur A M, Jordaens Luc J, Bezzina Connie R
Heart Failure Research Center, Department of Experimental Cardiology, Amsterdam, The Netherlands.
Circ Cardiovasc Genet. 2011 Jun;4(3):280-7. doi: 10.1161/CIRCGENETICS.110.959221. Epub 2011 Mar 15.
Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death.
We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication.
We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction-based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.
心脏传导疾病是一种临床和遗传异质性疾病，其特征为电冲动产生和传导缺陷，并与心源性猝死相关。
我们研究了一个四代常染色体显性遗传性进行性心脏传导疾病家系，包括房室传导阻滞和窦性心动过缓、房性心律失常以及猝死。全基因组连锁分析将疾病位点定位到1号染色体的1p22 - q21区域。对编码核膜蛋白核纤层蛋白A/C的LMNA基因进行多重连接依赖探针扩增分析，发现了一种新的基因重排，该重排涉及一个24bp的倒位，其上游有一个3.8kb的缺失，下游有一个7.8kb的缺失。断点连接处存在短的反向序列同源性，提示这是一个在DNA复制过程中涉及反式序列复制滑动的突变事件。
我们首次在一个患有进行性传导系统疾病的四代荷兰家系中鉴定出一种复杂的LMNA基因重排，涉及双重缺失。我们的研究结果强调，如果基于常规聚合酶链反应的LMNA分析直接测序方法在提示性家系中为阴性，那么应考虑采用能够检测涉及缺失和插入的大片段基因组病变的突变检测技术。
