Waiting in anticipation: the genetics of pulmonary arterial hypertension.
Waiting in anticipation: the genetics of pulmonary arterial hypertension.
复制标题
期待中的等待：肺动脉高压的遗传学。
DOI：
10.1164/rccm.201209-1666ed
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发表时间：
2012
影响因子：
24.7
通讯作者：
Morrell,NicholasW
中科院分区：
文献类型：
--
作者：
Aldred,MichealaA;Morrell,NicholasW
遗传预测是一种常染色体显性遗传疾病的发病年龄随着每一代的延续而变早的现象。表现出预期的遗传性疾病通常是由三联重复扩增引起的，三联重复扩增是三个碱基的串联重复序列，例如（CAG）n。这样的序列通常在一般人群中显示可变数量的重复，但当它们扩展超过一定阈值时变得致病。也许这方面最引人注目的例子是强直性肌营养不良，由3！- DMPK基因的非翻译区。在三代的空间中，该序列可以从与迟发性疾病相关的轻度致病性突变演变为导致非常严重的先天性形式的重复元件的大规模扩展（1）。重复扩增的倾向也取决于传播父母的性别，先天性形式主要与母体传播有关（2）。家族性肺动脉高压（PAH）是一种常染色体显性遗传疾病，遗传率降低，这意味着不是每个继承致病基因的人都会实际患上这种疾病，它可能完全跳过一个或多个世代。更复杂的是，女性比男性更容易发生性行为。尽管如此，PAH可能表现出预期性，儿童期发病病例突然发生在以前表现出更典型的中年发病的家庭中（3）。这导致了PAH可能是由三联重复突变引起的建议（4）。然而，当骨形态发生蛋白受体II（BMPR 2）基因被确定为家族性PAH的主要原因时（5，6），很明显，突变谱是大多数遗传性疾病中常见的错义、无义和移码突变的常规混合。由于没有分子解释，PAH的预期原因仍然是一个谜。在本期杂志中，Larkin和他的同事们（pp. 892-896）对来自范德比尔特大学登记处的53个PAH家族进行了重新分析（7）。他们假设，感知到的预期实际上可能是一种确认偏差，因为在最近几代人中，只有早发性病例才是明显的。需要延长观察期，以确定其他可能在以后的生活中仍然发展PAH的个体。因此，他们专注于BMPR 2突变的家庭，只考虑1955年之前出生的人。来自登记研究的证据表明，90%的病例在55岁时被诊断出来，因此通过这种方式，他们可以获得几乎完全确定的可能发展为PAH的个体。如果没有这种校正，平均诊断年龄在几代人之间明显下降，而年龄截断数据消除了这种差异。这种基于诊断年龄的方法的一个局限性是，根据定义，只有受影响的个体被包括在分析中;携带突变基因但从未患上疾病的未受影响的个体不包括在内。
Genetic anticipation is a phenomenon in which the age of onset of an autosomal dominant disease becomes earlier with each successive generation. Inherited diseases that show anticipation are most often caused by triplet repeat expansions, tandemly repeated sequences of three bases, for example (CAG) n. Such sequences typically show a variable number of repeats in the general population but become pathogenic when they expand beyond a certain threshold. Perhaps the most striking example of this is myotonic dystrophy, caused by a CTG repeat sequence in the 3!-untranslated region of the DMPK gene. In the space of three generations, this sequence can evolve from a mildly pathogenic mutation associated with late-onset disease to a massive expansion of the repeat element that causes a very severe congenital form (1). The propensity for repeat expansion is also dependent on the sex of the transmitting parent, the congenital form being mainly associated with maternal transmission (2). The familial form of pulmonary arterial hypertension (PAH) is inherited as an autosomal dominant condition with reduced penetrance, meaning that not everyone who inherits the causative gene will actually develop the disease and it may completely skip one or more generations. A further complexity is that the penetrance is higher in females than males. Despite this, PAH may appear to show anticipation, with childhood-onset cases suddenly occurring in families that previously showed the more typical onset in the middle decades of life (3). This led to the suggestion that PAH might be caused by a triplet repeat mutation (4). However, when the bone morphogenetic protein receptor II (BMPR2) gene was identified as the major cause of familial PAH (5, 6), it became clear that the mutation spectrum was the regular mix of missense, nonsense, and frameshift mutations seen in the majority of genetic diseases. With no molecular explanation, the cause of anticipation in PAH has remained an enigma. In this issue of the Journal, Larkin and colleagues (pp. 892–896) present a reanalysis of 53 PAH families from the registry at Vanderbilt University (7). They hypothesized that the perceived anticipation could in fact be an ascertainment bias because in the most recent generations, only the early-onset cases would be apparent. An extended period of observation would be required to ascertain other individuals who might still develop PAH later in life. They therefore focused on families with BMPR2 mutations and considered only individuals who were born before 1955. Evidence from the registry suggests that 90% of cases are diagnosed by age 55, so in this way they could obtain almost full ascertainment of individuals who were ever likely to develop PAH. Without this correction, the average age of diagnosis clearly decreased across the generations, whereas the age-truncated data eliminated this difference. One limitation of this approach based on age of diagnosis is that, by definition, only affected individuals are included in the analysis; unaffected individuals who carried the mutant gene but never developed the disease were not