Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, USA.
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, USA.
Brain. 2020 Apr 1;143(4):1099-1105. doi: 10.1093/brain/awaa051.
A large fraction of rare and severe neurodevelopmental disorders are caused by sporadic de novo variants. Epidemiological disease estimates are not available for the vast majority of these de novo monogenic neurodevelopmental disorders because of phenotypic heterogeneity and the absence of large-scale genomic screens. Yet, knowledge of disease incidence is important for clinicians and researchers to guide health policy planning. Here, we adjusted a statistical method based on genetic data to predict, for the first time, the incidences of 101 known de novo variant-associated neurodevelopmental disorders as well as 3106 putative monogenic disorders. Two corroboration analyses supported the validity of the calculated estimates. First, greater predicted gene-disorder incidences positively correlated with larger numbers of pathogenic variants collected from patient variant databases (Kendall's τ = 0.093, P-value = 6.9 × 10-6). Second, for six of seven (86%) de novo variant associated monogenic disorders for which epidemiological estimates were available (SCN1A, SLC2A1, SALL1, TBX5, KCNQ2, and CDKL5), the predicted incidence estimates matched the reported estimates. We conclude that in the absence of epidemiological data, our catalogue of 3207 incidence estimates for disorders caused by de novo variants can guide patient advocacy groups, clinicians, researchers, and policymakers in strategic decision-making.
大量罕见且严重的神经发育障碍是由散发性新生变异引起的。由于表型异质性和缺乏大规模基因组筛查，绝大多数新生单基因神经发育障碍疾病都没有流行病学疾病估计值。然而，疾病发病率的知识对于指导临床医生和研究人员制定卫生政策规划非常重要。在这里，我们调整了一种基于遗传数据的统计方法，首次预测了 101 种已知新生变异相关神经发育障碍和 3106 种推定单基因疾病的发病率。两项验证分析支持了计算出的估计值的有效性。首先，更多预测的基因-疾病发病率与从患者变异数据库中收集的致病性变异数量呈正相关（Kendall's τ=0.093，P 值=6.9×10-6）。其次，对于六种（86%）已知具有流行病学估计值的新生变异相关单基因疾病（SCN1A、SLC2A1、SALL1、TBX5、KCNQ2 和 CDKL5），预测的发病率估计值与报告的估计值相符。我们的结论是，在没有流行病学数据的情况下，我们的 3207 种由新生变异引起的疾病的发病率估计目录可以为患者权益团体、临床医生、研究人员和政策制定者在战略决策中提供指导。
