Department of Clinical Genetics (E.A.N., J.P.v.T., I.C.), Academic Medical Center, Amsterdam, The Netherlands.
AMC Heart Centre, Department of Clinical and Experimental Cardiology (I.A.W.v.R., A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.
Circ Genom Precis Med. 2018 Oct;11(10):e001797. doi: 10.1161/CIRCGEN.117.001797.
Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation.
We collected mortality data from mutation-positive subjects with either DPP6-associated idiopathic ventricular fibrillation, SCN5A overlap syndrome, and PLN-R14del-mediated arrhythmogenic cardiomyopathy >2 to 10 years of ongoing clinical/cascade genetic screening.
The median age of survival in DPP6 mutation-positive subjects increased from 44.6 years in the original cohort from 2008 (n=60; 95% CI, 36.8-52.4 years) to 68.2 years in the extended cohort from 2012 (n=235; 95% CI, 64.6-71.7 years; P<0.001). In the SCN5A overlap syndrome, survival increased from 56.1 years in 1999 (n=86; 95% CI, 48.0-64.2 years) to 69.7 years in 2009 (n=197; 95% CI, 61.3-78.2 years; P=0.049). In PLN-R14del positive patients, the median age of survival increased from 63.5 years in 2010 (n=89; 95% CI, 59.1-68.0 years) to 65.2 years in 2012 (n=370; 95% CI, 62.0-68.3 years; P=0.046).
The median age of survival in 3 different inherited cardiac diseases with an established pathogenic substrate significantly increased once genetic testing and cascade screening extended, after the first publication that elucidated the discovery of the disease-susceptibility gene/mutation. This underscores the direct and negative influence of ascertainment bias on survival forecasts and the importance of ongoing clinical/genetic follow-up to establish the most accurate disease prognosis for genetically mediated heart diseases.
对于处理遗传性心脏病患者的心脏病专家、临床遗传学家和遗传咨询师来说，准确的生存估计是必不可少的。然而，在最初的出版物中，对更严重疾病和更糟糕结局的偏倚可能无法准确反映实际的生存预测。因此，我们评估了在由一个突变引起的三种不同遗传性心脏病（特发性室性颤动、SCN5A 重叠综合征和致心律失常性右室心肌病）中，确定偏倚对生存的影响。
我们从具有 DPP6 相关特发性室性颤动、SCN5A 重叠综合征和 PLN-R14del 介导的致心律失常性右室心肌病的突变阳性患者中收集了 2 至 10 年的临床/级联遗传筛查后的死亡率数据。
DPP6 突变阳性患者的中位生存年龄从 2008 年最初队列中的 44.6 岁（n=60；95%CI，36.8-52.4 岁）增加到 2012 年扩展队列中的 68.2 岁（n=235；95%CI，64.6-71.7 岁；P<0.001）。在 SCN5A 重叠综合征中，生存年龄从 1999 年的 56.1 岁（n=86；95%CI，48.0-64.2 岁）增加到 2009 年的 69.7 岁（n=197；95%CI，61.3-78.2 岁；P=0.049）。在 PLN-R14del 阳性患者中，中位生存年龄从 2010 年的 63.5 岁（n=89；95%CI，59.1-68.0 岁）增加到 2012 年的 65.2 岁（n=370；95%CI，62.0-68.3 岁；P=0.046）。
在三种具有既定致病基础的遗传性心脏病中，一旦进行了基因检测和级联筛查，并且在阐明疾病易感性基因/突变的首次出版物之后，中位生存年龄显著增加。这突显了确定偏倚对生存预测的直接和负面影响，以及对遗传性心脏病进行持续临床/遗传随访以建立最准确疾病预后的重要性。
