GENOTYPE/PHENOTYPE STUDIES IN HYPERTROPHIC CARDIOMYOPATHY

肥厚型心肌病是最常见的遗传性心脏病 疾病。最近，β肌球蛋白重链(BetaMHC)基因已经 在大约一半的家庭中，与母婴传播疾病有关联。我们之前已经 报告说，BetaMHC基因的两个明显突变明显 不同的临床表现和预后：908Leu=&gt；Val突变 在270名肥厚型心肌病(HCM)成员中，有亲属关系 猝死(SD)发生率低，疾病外显率为61%。 然而，在一个19人(高加索人)家族中，403Arg=&gt；Gln突变是 与SD的高发病率和100%的疾病外显率有关。 最近，一个606Val=&gt；Met突变与“接近正常生存”有关 在3个小家庭中被报告并被提供作为证据 中性电荷替换的良性性质。我们报告1)a) 606Val=&gt；与4个受影响成员中出现的SD和2)a)相匹配 第二个(东方)家系，403Arg=&gt；Gln突变。虽然 403Arg=&gt；Gln在两个家族中都是严重的和早期的疾病 突变、心脏形态和血流动力学特征明显。合而为一 所有患者均为非梗阻性肥厚型心肌病，并有左室舒张功能。 在另一家系中，所有患者均有梗阻性肥厚心肌。 因此，1)必须使用大家族来判断突变是良性的，2) 蛋氨酸突变在某些家族中是恶性的，因此是轻微的 BetaMHC蛋白关键区域的替换也可能具有 严重的后果，以及3)两个403人的不同种族来源 血缘关系证明相同的突变是独立发生的 有两种不同的遗传背景。他们相似但又截然不同 表型强调了修饰基因的重要性。

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Recently, the betaeta myosin heavy chain (betaMHC) gene has been linked with HCM in about half of the kindreds. We have previously reported that two distinct mutations in the betaMHC gene had markedly different clinical presentations and prognoses: The 908Leu=>Val mutation in a 270 member hypertrophic cardiomyopathy (HCM) kindred was associated with a low incidence of sudden death (SD) and a 61% disease penetrance. The 403Arg=>Gln mutation however, in a 19-member (caucasian) kindred was associated with a high incidence of SD and 100% disease penetrance. Recently, a 606Val=>Met mutation, associated with "near normal survival" in 3 small kindreds has been reported and offered as evidence for the benign nature of neutral charge substitutions. We report 1) a 606Val=>Met kindred with 4 SD occurring in - affected members and 2) a second (oriental) kindred with the 403Arg=>Gln mutation. Although disease was severe and early in both kindreds with the 403Arg=>Gln mutation, cardiac morphology and hemodynamics were distinct. In one kindred all patients had non-obstructive HCM and LV diastolic dysfunction while in the other kindred all patients had obstructive HCM. Thus, 1) large kindreds must be used to judge a mutation benign, 2) 606Val=>Met mutation is malignant in some kindreds and hence minor substitutions in critical regions of betaMHC protein may also have serious consequences, and 3) the diverse ethnic origins of the two 403 kindreds is proof that the identical mutation had occurred independently on two different genetic backgrounds. Their similar yet distinct phenotype underlines the importance of modifying genes.