Epstein N D, Cohn G M, Cyran F, Fananapazir L
Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Circulation. 1992 Aug;86(2):345-52. doi: 10.1161/01.cir.86.2.345.
The disease gene for hypertrophic cardiomyopathy (HCM) has been identified as the beta-myosin heavy chain (beta-MHC) gene in some HCM families. We describe extensive clinical evaluations in two kindreds with two distinct point mutations in the beta-MHC gene.
We used single-strand confirmation polymorphism (SSCP) gel analysis of polymerase chain reaction-amplified products capturing each of the 40 beta-MHC gene exons to identify distinct missense mutations in two HCM kindreds. Clinical, ECG, and echocardiographic studies were performed in the two kindreds: kindred 2755 with amino acid 908Leu----Val mutation and kindred 2002 with amino acid 403Arg----Gln mutation. The morphological appearances of HCM were similar in these two kindreds. However, the two kindreds differed with respect to disease penetrance, age of onset of disease, and incidence of premature sudden death. Twelve of 31 adults (greater than or equal to 17 years) with the disease gene in kindred 2755 did not have left ventricular hypertrophy (LVH), and only five of these had ECG abnormalities. Thus, the disease penetrance in adults with this mutation was only 61%. None of 11 children aged less than 16 years had LVH. The 908 mutation was associated with a low incidence of cardiac events: Only two sudden deaths and one syncope occurred in 46 individuals with the mutant allele. In contrast, LVH was present in all 11 adults in kindred 2002 with the 403 mutation (100% disease penetrance). In addition, three of four affected children were symptomatic and had clinical evidence of HCM. The disease in this kindred was severe and resulted in six premature sudden deaths. Seven additional patients had syncope or presyncope.
In some kindreds, the HCM disease gene is more prevalent than indicated by echocardiography and ECG. Some point mutations may be associated with a more malignant prognosis. Preclinical identification of children with mutations associated with a high incidence of sudden death and syncope provides the opportunity to evaluate efficacy of early therapeutic interventions.
在一些肥厚型心肌病（HCM）家族中，已确定肥厚型心肌病的致病基因是β-肌球蛋白重链（β-MHC）基因。我们描述了对两个携带β-MHC基因不同点突变的家族进行的广泛临床评估。
我们对聚合酶链反应扩增产物进行单链构象多态性（SSCP）凝胶分析，该扩增产物涵盖了β-MHC基因的40个外显子，以确定两个HCM家族中的不同错义突变。对这两个家族进行了临床、心电图和超声心动图研究：家族2755存在氨基酸908Leu→Val突变，家族2002存在氨基酸403Arg→Gln突变。这两个家族中HCM的形态学表现相似。然而，这两个家族在疾病外显率、发病年龄和过早猝死发生率方面存在差异。家族2755中31名携带致病基因的成年人（≥17岁）中有12人没有左心室肥厚（LVH），其中只有5人有心电图异常。因此，携带这种突变的成年人的疾病外显率仅为61%。11名年龄小于16岁的儿童均无LVH。908突变与心脏事件发生率低相关：在46名携带突变等位基因的个体中，仅发生了2例猝死和1例晕厥。相比之下，家族2002中所有11名携带403突变的成年人都有LVH（疾病外显率100%）。此外，4名受影响儿童中有3名有症状且有HCM的临床证据。这个家族的疾病很严重，导致6例过早猝死。另外7名患者有晕厥或先兆晕厥。
在一些家族中，HCM致病基因比超声心动图和心电图显示的更为普遍。一些点突变可能与更恶性的预后相关。对与猝死和晕厥高发生率相关的突变儿童进行临床前鉴定，为评估早期治疗干预的疗效提供了机会。
