With the advent and widespread adoption of high-throughput DNA sequencing, genetic discoveries in neurodevelopmental disorders (NDDs) are advancing very rapidly. The identification of novel NDD genes and of rare, highly penetrant pathogenic variants is leading to improved understanding of genotype–phenotype correlations. Here we emphasize the importance of large-scale, reference databases such as gnomAD to determine gene and variant level constraints and facilitate gene discovery, variant interpretation, and genotype–phenotype correlations. While the majority of dominant NDD genes are highly intolerant to variation, some apparent exceptions in reference databases are related to the presence of variants in transcripts that are not brain expressed and/or genes that show acquired somatic mosaicism in blood. Multiple NDD genes are being identified where varying phenotypes depend on the mode of inheritance (e.g., dominant or recessive), the nature (e.g., missense or truncating), or location of the mutation. Ongoing genome-wide analyses and targeted functional studies provide enhancements to the annotation of genes, gene products and variants, which will continue to facilitate gene and variant discovery and variant interpretation.

随着高通量 DNA 测序的出现和广泛采用，神经发育障碍 (NDD) 的遗传发现进展非常迅速。新型 NDD 基因和罕见、高渗透性致病变异的鉴定正在提高对基因型-表型相关性的理解。在这里，我们强调大型参考数据库（例如 gnomAD）对于确定基因和变异水平限制并促进基因发现、变异解释和基因型-表型相关性的重要性。虽然大多数显性 NDD 基因对变异高度不耐受，但参考数据库中的一些明显例外与非大脑表达的转录物变异的存在和/或在血液中显示获得性体细胞嵌合的基因有关。正在鉴定多个 NDD 基因，其中不同的表型取决于遗传模式（例如显性或隐性）、性质（例如错义或截短）或突变位置。正在进行的全基因组分析和有针对性的功能研究增强了基因、基因产物和变异的注释，这将继续促进基因和变异的发现以及变异的解释。