Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Rare Disease and Medical Genetics, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, Italy.
Nat Commun. 2020 Oct 1;11(1):4932. doi: 10.1038/s41467-020-18723-y.
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
大多数与神经发育障碍（NDD）相关的基因都与新生突变（DNMs）过多有关，但在病例对照突变负担分析中的意义尚未确定。在这里，我们对 16294 例 NDD 病例中的 63 个基因和另外 6211 例 NDD 病例中的 62 个基因进行了测序。通过将这些数据与已发表的数据相结合，我们评估了超过 16000 例 NDD 病例中的 125 个基因，并将突变负担与 ExAC 中的非精神科对照进行了比较。我们确定了 48 个基因（其中 25 个是新报告的）显示出超稀有（MAF < 0.01%）基因破坏性突变的显著负担（FDR 5%），其中 6 个达到了全错误率（FWER）的显著水平（p < 1.25E-06）。在这 125 个靶向基因中，我们还在 17426 个 NDD 三体型病例中重新评估了 6499 个新的自闭症三体型病例中的 DNM 过剩。我们确定了 90 个基因富含 DNMs（FDR 5%；例如，GABRG2 和 UIMC1）；其中，61 个达到了 FWER 显著水平（p < 3.64E-07；例如，CASZ1）。除了为许多 NDD 风险基因的患者数量增加了一倍外，我们还根据这项大规模靶向测序工作，为七个风险基因（CTCF、HNRNPU、KCNQ3、ZBTB18、TCF12、SPEN 和 LEO1）提供了表型-基因型相关性。
