Li Kuokuo, Ling Zhengbao, Luo Tengfei, Zhao Guihu, Zhou Qiao, Wang Xiaomeng, Xia Kun, Li Jinchen, Li Bin
National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, China.
Life (Basel). 2021 Mar 12;11(3):233. doi: 10.3390/life11030233.
De novo variants (DNVs) are critical to the treatment of neurodevelopmental disorders (NDDs). However, effectively identifying candidate genes in small cohorts is challenging in most NDDs because of high genetic heterogeneity. We hypothesised that integrating DNVs from multiple NDDs with genetic similarity can significantly increase the possibility of prioritising the candidate gene. We catalogued 66,186 coding DNVs in 50,028 individuals with nine types of NDDs in cohorts with sizes spanning from 118 to 31,260 from Gene4Denovo database to validate this hypothesis. Interestingly, we found that integrated DNVs can effectively increase the number of prioritised candidate genes for each disorder. We identified 654 candidate genes including 481 shared candidate genes carrying putative functional variants in at least two disorders. Notably, 13.51% (65/481) of shared candidate genes were prioritised only via integrated analysis including 44.62% (29/65) genes validated in recent large cohort studies. Moreover, we estimated that more novel candidate genes will be prioritised with the increase in cohort size, in particular for some disorders with high putative functional DNVs per individual. In conclusion, integrated DNVs may increase the power of prioritising candidate genes, which is important for NDDs with small cohort size.
新发变异（DNV）对于神经发育障碍（NDD）的治疗至关重要。然而，由于遗传异质性高，在大多数NDD中，在小样本队列中有效识别候选基因具有挑战性。我们假设，整合来自多个具有遗传相似性的NDD的DNV可以显著提高对候选基因进行优先级排序的可能性。我们从Gene4Denovo数据库中梳理了50,028名患有九种类型NDD的个体中的66,186个编码DNV，这些个体来自规模从118到31,260不等的队列，以验证这一假设。有趣的是，我们发现整合后的DNV可以有效增加每种疾病中优先级候选基因的数量。我们鉴定出654个候选基因，其中包括481个在至少两种疾病中携带推定功能变异的共享候选基因。值得注意的是，13.51%（65/481）的共享候选基因仅通过整合分析被列为优先级，其中44.62%（29/65）的基因在最近的大型队列研究中得到了验证。此外，我们估计随着队列规模的增加，会有更多新的候选基因被列为优先级，特别是对于一些每个个体中推定功能DNV较高的疾病。总之，整合DNV可能会提高对候选基因进行优先级排序的能力，这对于小样本队列的NDD来说很重要。
