Omics Research Center (T.I., N.M.), National Cerebral and Cardiovascular Center, Suita, Japan.
Department of Human Genetics (H.M., K.-I.Y.), Nagasaki University Graduate School of Biomedical Sciences, Japan.
Circ Arrhythm Electrophysiol. 2020 Oct;13(10):e008712. doi: 10.1161/CIRCEP.120.008712. Epub 2020 Jul 29.
Mutations in the nuclear envelope genes encoding and are responsible for Emery-Dreifuss muscular dystrophy. However, mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with mutations.
Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51).
We identified 3 X-linked recessive mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with has never been reported, we further genetically screened 102 LVNC patients and found a frameshift mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC.
Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.
核包膜基因 和 突变是导致 Emery-Dreifuss 肌营养不良症的原因。然而， 突变常表现为扩张型心肌病伴传导障碍，而无明显的骨骼肌肌病并发症。相反， 突变的表型谱不太清楚。我们的目的是确定可能是遗传上未定义的孤立性心脏传导障碍的隐性 Emery-Dreifuss 肌营养不良症的患病率，以及与 突变相关的血栓栓塞并发症的病因。
对 87 名有家族性病态窦房结综合征（n=36）和进行性心脏传导障碍（n=51）的先证者进行靶向外显子测序。
我们在有心脏传导疾病的家族中发现了 3 个 X 连锁隐性 突变（起始缺失、剪接、错义）。所有 3 个先证者都有共同的临床表型，即进行性房性心律失常，最终导致与左心室致密化不全（LVNC）相关的房性静止，但他们缺乏 Emery-Dreifuss 肌营养不良症的早期挛缩和进行性肌肉消瘦和无力。由于 LVNC 与 之间的关联从未被报道过，我们进一步对 102 例 LVNC 患者进行了基因筛查，发现 1 名男孩有进行性房性静止和 LVNC，但没有肌肉营养不良的并发症，携带 突变。4 个家族的 6 名男性 突变携带者都接受了起搏器或除颤器植入，而 2 名女性携带者无症状。值得注意的是，这些家族中观察到的强烈的中风家族史可能是由于房性静止和 LVNC 导致的血栓栓塞风险增加所致。
心脏性弹力蛋白病是一种新型的非综合征性 X 连锁进行性房性静止，与 LVNC 和增加的血栓栓塞风险相关。
