Kawakami Hiroshi, Ogimoto Akiyoshi, Tokunaga Naohito, Nishimura Kazuhisa, Kawakami Hideo, Higashi Haruhiko, Iio Chiharuko, Kono Tamami, Aono Jun, Uetani Teruyoshi, Nagai Takayuki, Inoue Katsuji, Suzuki Jun, Ikeda Shuntaro, Okura Takafumi, Ohyagi Yasumasa, Tabara Yasuharu, Higaki Jitsuo
Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine.
Department of Cardiology, Ehime Prefectural Imabari Hospital.
Int Heart J. 2018 May 30;59(3):531-541. doi: 10.1536/ihj.17-377. Epub 2018 May 6.
The cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM.Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular disease-associated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.
核纤层蛋白病的心脏表型特征为心脏传导障碍（CCD）和扩张型心肌病（DCM）。尽管核纤层蛋白病被认为是单基因疾病，但它们表现出显著程度的临床变异性。本病例系列旨在检测致病突变，并调查一个患有遗传性CCD和DCM的日本家族中临床变异性的原因。在调查的五名家庭成员中，四名患有CCD/DCM或仅患有CCD，而一名受试者没有心血管疾病，作为正常对照。我们对这个家族中174个与遗传性心血管疾病相关的基因进行了靶向重测序，并使用桑格测序法确认了病理性突变。还使用长期医疗记录评估了临床严重程度和变异性。我们在所有四名患有CCD的受试者中发现了一种新的杂合性截短型核纤层蛋白A/C（LMNA）突变（c.774delG）。由于该突变预计会导致LMNA发生移码突变和提前终止（p.Gln258HisfsTer222），我们认为这种LMNA突变是这个患有CCD和核纤层蛋白病的家族中的致病突变。此外，在这个日本家族中观察到了家族内性别特异性的临床变异性，其中受影响的男性与受影响的女性相比，CCD发病更早，DCM更严重。通过靶向重测序，我们在这个家族中发现了一种与CCD和DCM相关的新的截短型LMNA突变，其特征是LMNA携带者的临床严重程度存在性别差异。我们的结果表明，在核纤层蛋白病患者中，临床严重程度可能是多种因素导致的。
